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Sample records for actual genome-wide single-nucleotide

  1. Swedish population substructure revealed by genome-wide single nucleotide polymorphism data.

    Elina Salmela

    Full Text Available The use of genome-wide single nucleotide polymorphism (SNP data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes--especially southern Swedes--were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced genetic differences both within the area and relative to the rest of the country. These distinctive genetic features of Norrland probably result mainly from isolation by distance and genetic drift caused by low population density. The internal structure within Sweden (F(ST = 0.0005 between provinces was stronger than that in many Central European populations, although smaller than what has been observed for instance in Finland; importantly, it is of the magnitude that may hamper association studies with a moderate number of markers if cases and controls are not properly matched geographically. Overall, our results underline the potential of genome-wide data in analyzing substructure in populations that might otherwise appear relatively homogeneous, such as the Swedes.

  2. Use of Genome-wide Heterospecific Single-Nucleotide Polymorphisms to Estimate Linkage Disequilibrium in Rhesus and Cynomolgus Macaques

    Ng, Jillian; Trask, Jessica Satkoski; Houghton, Paul; Smith, David G.; Kanthaswamy, Sree

    2015-01-01

    Rhesus and cynomolgus macaques are frequently used in biomedical research, and the availability of their reference genomes now provides for their use in genome-wide association studies. However, little is known about linkage disequilibrium (LD) in their genomes, which can affect the design and success of such studies. Here we studied LD by using 1781 conserved single-nucleotide polymorphisms (SNPs) in 183 rhesus macaques (Macaca mulatta), including 97 purebred Chinese and 86 purebred Indian a...

  3. Finding type 2 diabetes causal single nucleotide polymorphism combinations and functional modules from genome-wide association data

    Kang, Chiyong; Yu, Hyeji; Yi, Gwan-Su

    2013-01-01

    Background Due to the low statistical power of individual markers from a genome-wide association study (GWAS), detecting causal single nucleotide polymorphisms (SNPs) for complex diseases is a challenge. SNP combinations are suggested to compensate for the low statistical power of individual markers, but SNP combinations from GWAS generate high computational complexity. Methods We aim to detect type 2 diabetes (T2D) causal SNP combinations from a GWAS dataset with optimal filtration and to di...

  4. Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays.

    Rani E George

    Full Text Available BACKGROUND: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP array. FINDINGS: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%. Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016. Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95% and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. CONCLUSIONS: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy.

  5. Genome-wide single nucleotide polymorphism array analysis reveals recurrent genomic alterations associated with histopathologic features in intrahepatic cholangiocarcinoma

    Huang, Wan-Ting; Weng, Shao-Wen; Wei, Yu-Ching; You, Huey-Ling; Wang, Jui-Tzu; Eng, Hock-Liew

    2014-01-01

    Recent studies indicate that genomic alterations (GAs) are associated with many human malignancies. Genome-wide analysis of GAs involved in intrahepatic cholangiocarcinoma (ICC) and association with histopathologic features are limited. To help characterize this relatively rare neoplasm, we collected 32 frozen tissue samples of ICC to study GAs and molecular karyotypes by using single-nucleotide polymorphism array. Recurrent GAs occurring in at least 40% of the patients were further correlated with histopathologic features. Gain of 1q21.3-q23.1 and losses of 1p36.33-p35.3 and 3p26.3-p13 were significantly associated with larger tumor size more than 5 cm in diameter; and loss of 4q13.2-q35.2 with tumor multiplicity. Moreover, losses of 1p36.32-p35.3, 3p26.3-p22.2, 4q13.1-q21.23, 4q31.3-q34.3 and 4q34.3-35.2 were inclined to be associated with high histological grade. As to tumor vascular invasion, gain of 1q21.3-q23.1 and losses of 3p22.1-p12.3 and 4q13.2-q35.2 were significantly associated with tumor vascular invasion. Some regions were concurrently associated with multiple histopathologic characteristics, including loss of 4q13.2-q35.2 associated with larger tumor size, high histological grade and vascular invasion; losses of 1p36.33-p35.3 and 3p26.3-p22.2 with larger tumor size and high histological grade; and gain of 1q21.3-q23.1 with larger tumor size and vascular invasion. Our study indicates that complex chromosomal instability is characteristic of ICC. Detecting crucial GAs will enable risk stratification and development of personalized therapies. PMID:25400767

  6. False-Negative-Rate Based Approach for Selecting Top Single-Nucleotide Polymorphisms in the First Stage of a Two-Stage Genome-Wide Association Study

    Huang, Zhuying; Wang, Jian; Wu, Chih-Chieh; Richard S Houlston; Bondy, Melissa L.; Shete, Sanjay

    2011-01-01

    Genome-wide association (GWA) studies, where hundreds of thousands of single-nucleotide polymorphisms (SNPs) are tested simultaneously, are becoming popular for identifying disease loci for common diseases. Most commonly, a GWA study involves two stages: the first stage includes testing the association between all SNPs and the disease and the second stage includes replication of SNPs selected from the first stage to validate associations in an independent sample. The first stage is considered...

  7. Word Reading Fluency: Role of Genome-Wide Single-Nucleotide Polymorphisms in Developmental Stability and Correlations with Print Exposure

    Harlaar, Nicole; Trzaskowski, Maciej; Dale, Philip S.; Plomin, Robert

    2014-01-01

    The genetic effects on individual differences in reading development were examined using genome-wide complex trait analysis (GCTA) in a twin sample. In unrelated individuals (one twin per pair, n = 2,942), the GCTA-based heritability of reading fluency was ~20%-29% at ages 7 and 12. GCTA bivariate results showed that the phenotypic stability of…

  8. Signatures of selection in the Iberian honey bee: a genome wide approach using single nucleotide polymorphisms (SNPs)

    Chavez-Galarza, Julio; Johnston, J. Spencer; Azevedo, João; Muñoz, Irene; De La Rúa, Pilar; Patton, John C.; Pinto, M. Alice

    2011-01-01

    Dissecting genome-wide (expansions, contractions, admixture) from genome-specific effects (selection) is a goal of central importance in evolutionary biology because it leads to more robust inferences of demographic history and to identification of adaptive divergence. The publication of the honey bee genome and the development of high-density SNPs genotyping, provide us with powerful tools, allowing us to identify signatures of selection in the honey bee genome. These signatures will be an i...

  9. Genome-wide dynamic transcriptional profiling in clostridium beijerinckii NCIMB 8052 using single-nucleotide resolution RNA-Seq

    Wang Yi

    2012-03-01

    Full Text Available Abstract Background Clostridium beijerinckii is a prominent solvent-producing microbe that has great potential for biofuel and chemical industries. Although transcriptional analysis is essential to understand gene functions and regulation and thus elucidate proper strategies for further strain improvement, limited information is available on the genome-wide transcriptional analysis for C. beijerinckii. Results The genome-wide transcriptional dynamics of C. beijerinckii NCIMB 8052 over a batch fermentation process was investigated using high-throughput RNA-Seq technology. The gene expression profiles indicated that the glycolysis genes were highly expressed throughout the fermentation, with comparatively more active expression during acidogenesis phase. The expression of acid formation genes was down-regulated at the onset of solvent formation, in accordance with the metabolic pathway shift from acidogenesis to solventogenesis. The acetone formation gene (adc, as a part of the sol operon, exhibited highly-coordinated expression with the other sol genes. Out of the > 20 genes encoding alcohol dehydrogenase in C. beijerinckii, Cbei_1722 and Cbei_2181 were highly up-regulated at the onset of solventogenesis, corresponding to their key roles in primary alcohol production. Most sporulation genes in C. beijerinckii 8052 demonstrated similar temporal expression patterns to those observed in B. subtilis and C. acetobutylicum, while sporulation sigma factor genes sigE and sigG exhibited accelerated and stronger expression in C. beijerinckii 8052, which is consistent with the more rapid forespore and endspore development in this strain. Global expression patterns for specific gene functional classes were examined using self-organizing map analysis. The genes associated with specific functional classes demonstrated global expression profiles corresponding to the cell physiological variation and metabolic pathway switch. Conclusions The results from this

  10. Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

    Mayuko Tamura

    Full Text Available Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR gene. No patients have been reported with uniparental disomy (UPD.Using genome-wide single nucleotide polymorphism (SNP array to confirm whether HVDRR was caused by UPD of chromosome 12.A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.

  11. A genome-wide association study identifies novel single nucleotide polymorphisms associated with dermal shank pigmentation in chickens.

    Li, Guangqi; Li, Dongfeng; Yang, Ning; Qu, Lujiang; Hou, Zhuocheng; Zheng, Jiangxia; Xu, Guiyun; Chen, Sirui

    2014-12-01

    Shank color of domestic chickens varies from black to blue, green, yellow, or white, which is controlled by the combination of melanin and xanthophylls in dermis and epidermis. Dermal shank pigmentation of chickens is determined by sex-linked inhibitor of dermal melanin (Id), which is located on the distal end of the long arm of Z chromosome, through controlling dermal melanin pigmentation. Although previous studies have focused on the identification of Id and the linear relationship with barring and recessive white skin, no causal mutations have yet been identified in relation to the mutant dermal pigment inhibiting allele at the Id locus. In this study, we first used the 600K Affymetrix Axiom HD genotyping array, which includes ~580,961 SNP of which 26,642 SNP were on the Z chromosome to perform a genome-wide association study on pure lines of 19 Tibetan hens with dermal pigmentation shank and 21 Tibetan hens with yellow shank to refine the Id location. Association analysis was conducted by the PLINK software using the standard chi-squared test, and then Bonferroni correction was used to adjust multiple testing. The genome-wide study revealed that 3 SNP located at 78.5 to 79.2 Mb on the Z chromosome in the current assembly of chicken genome (galGal4) were significantly associated with dermal shank pigmentation of chickens, but none of them were located in known genes. The interval we refined was partly converged with previous results, suggesting that the Id gene is in or near our refined genome region. However, the genomic context of this region was complex. There were only 15 SNP markers developed by the genotyping array within the interval region, in which only 1 SNP marker passed quality control. Additionally, there were about 5.8-Mb gaps on both sides of the refined interval. The follow-up replication studies may be needed to further confirm the functional significance for these newly identified SNP. PMID:25260525

  12. A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 × 10−5 to 6.2 × 10−4). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers’ D P value = 1.7 × 10−29). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 × 10−19). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

  13. A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

    Kerns, Sarah L. [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Stock, Richard [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Stone, Nelson [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Department of Urology, Mount Sinai School of Medicine, New York, New York (United States); Buckstein, Michael [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Shao, Yongzhao [Division of Biostatistics, New York University School of Medicine, New York, New York (United States); Campbell, Christopher [Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Rath, Lynda [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); De Ruysscher, Dirk; Lammering, Guido [Department of Radiation Oncology, Maastricht University Medical Center, Maastricht (Netherlands); Hixson, Rosetta; Cesaretti, Jamie; Terk, Mitchell [Florida Radiation Oncology Group, Jacksonville, Florida (United States); Ostrer, Harry [Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Rosenstein, Barry S., E-mail: barry.rosenstein@mssm.edu [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Departments of Dermatology and Preventive Medicine, Mount Sinai School of Medicine, New York, New York (United States)

    2013-01-01

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 Multiplication-Sign 10{sup -5} to 6.2 Multiplication-Sign 10{sup -4}). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 Multiplication-Sign 10{sup -29}). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 Multiplication-Sign 10{sup -19}). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

  14. Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. Methods and Materials: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score ≤7) and 52 control subjects (post-treatment SHIM score ≥16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). Results: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 x 10-8, Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value -6. Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. Conclusions: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the

  15. Genome-wide association study of preeclampsia detects novel maternal single nucleotide polymorphisms and copy-number variants in subsets of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort

    Zhao, Linlu; Bracken, Michael B; DeWan, Andrew T

    2013-01-01

    A genome-wide association study was undertaken to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) associated with preeclampsia. Case-control analysis was performed on 1070 Afro-Caribbean (n=21 cases and 1049 controls) and 723 Hispanic (n=62 cases and 661 controls) mothers and 1257 mothers of European ancestry (n=50 cases and 1207 controls) from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. European ancestry subjects were genotyped on Il...

  16. A genome-wide association study for milk production traits in Danish Jersey cattle using a 50K single nucleotide polymorphism chip

    Mai, Duy Minh; Sahana, Goutam; Christiansen, Freddy;

    2010-01-01

    milk index, 50 for fat index, and 18 for protein index. The evidence presents 33 genome-wide QTL on 14 BTA. Of these, 7 had effects on milk index, 21 on fat index, and 5 on protein index. Among the genome-wide QTL, 26 have been previously reported, 2 on BTA4 and BTA5 were new for milk index, and 5 on...

  17. Cacao single-nucleotide polymorphism (SNP) markers: A discovery strategy to identify SNPs for genotyping, genetic mapping and genome wide association studies (GWAS)

    Single-nucleotide polymorphisms (SNPs) are the most common genetic markers in Theobroma cacao, occurring approximately once in every 200 nucleotides. SNPs, like microsatellites, are co-dominant and PCR-based, but they have several advantages over microsatellites. They are unambiguous, so that a SN...

  18. Genome-wide association study of preeclampsia detects novel maternal single nucleotide polymorphisms and copy-number variants in subsets of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study cohort

    Zhao, Linlu; Bracken, Michael B.; DeWan, Andrew T.

    2013-01-01

    Summary A genome-wide association study was undertaken to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) associated with preeclampsia. Case-control analysis was performed on 1070 Afro-Caribbean (n=21 cases and 1049 controls) and 723 Hispanic (n=62 cases and 661 controls) mothers and 1257 mothers of European ancestry (n=50 cases and 1207 controls) from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. European ancestry subjects were genotyped on Illumina Human610-Quad and Afro-Caribbean and Hispanic subjects were genotyped on Illumina Human1M-Duo BeadChip microarrays. Genome-wide SNP data were analyzed using PLINK. CNVs were called using three detection algorithms (GNOSIS, PennCNV, and QuantiSNP), merged using CNVision, and then screened using stringent criteria. SNP and CNV findings were compared to those of the Study of Pregnancy Hypertension in Iowa (SOPHIA), an independent preeclampsia case-control dataset of Caucasian mothers (n=177 cases and 116 controls). A list of top SNPs were identified for each of the HAPO ethnic groups, but none reached Bonferroni-corrected significance. Novel candidate CNVs showing enrichment among preeclampsia cases were also identified in each of the three ethnic groups. Several variants were suggestively replicated in SOPHIA. The discovered SNPs and copy-number variable regions present interesting candidate genetic variants for preeclampsia that warrant further replication and investigation. PMID:23551011

  19. The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies

    Zhang Jinghui

    2007-10-01

    Full Text Available Abstract Background We studied linkage disequilibrium (LD patterns at the BRCA1 locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient. Results BRCA1 is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG. Conclusion Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCA1 in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations.

  20. Association study of nonsynonymous single nucleotide polymorphisms in schizophrenia

    Carrera, Noa; Arrojo, Manuel; Sanjuán, Julio;

    2012-01-01

    Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem...

  1. Use of Longitudinal Data in Genetic Studies in the Genome-wide Association Studies Era: Summary of Group 14

    Kerner, Berit; North, Kari E; Fallin, M. Daniele

    2009-01-01

    Participants analyzed actual and simulated longitudinal data from the Framingham Heart Study for various metabolic and cardiovascular traits. The genetic information incorporated into these investigations ranged from selected single-nucleotide polymorphisms to genome-wide association arrays. Genotypes were incorporated using a broad range of methodological approaches including conditional logistic regression, linear mixed models, generalized estimating equations, linear growth curve estimatio...

  2. Genome-wide association study of multiplex schizophrenia pedigrees

    Levinson, Douglas F; Shi, Jianxin; Wang, Kai;

    2012-01-01

    The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs)....

  3. Single Nucleotide Polymorphism

    Børsting, Claus; Pereira, Vania; Andersen, Jeppe Dyrberg;

    2014-01-01

    Single nucleotide polymorphisms (SNPs) are the most frequent DNA sequence variations in the genome. They have been studied extensively in the last decade with various purposes in mind. In this chapter, we will discuss the advantages and disadvantages of using SNPs for human identification and...... briefly describe the methods that are preferred for SNP typing in forensic genetics. In addition, we will illustrate how SNPs can be used as investigative leads in the police investigation by discussing the use of ancestry informative markers and forensic DNA phenotyping. Modern DNA sequencing...

  4. Direct detection of single-nucleotide polymorphisms in bacterial DNA by SNPtrap

    Grønlund, Hugo Ahlm; Moen, Birgitte; Hoorfar, Jeffrey; Rådstrøm, Peter; Malorny, Burkhard; Rudi, Knut

    2011-01-01

    A major challenge with single-nucleotide polymorphism (SNP) fingerprinting of bacteria and higher organisms is the combination of genome-wide screenings with the potential of multiplexing and accurate SNP detection. Single-nucleotide extension by the minisequencing principle represents a technology...

  5. Systems-Level Analysis of Genome-Wide Association Data

    Farber, Charles R

    2013-01-01

    Genome-wide association studies (GWAS) have emerged as the method of choice for identifying common variants affecting complex disease. In a GWAS, particular attention is placed, for obvious reasons, on single-nucleotide polymorphisms (SNPs) that exceed stringent genome-wide significance thresholds. However, it is expected that many SNPs with only nominal evidence of association (e.g., P < 0.05) truly influence disease. Efforts to extract additional biological information from entire GWAS data...

  6. Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

    Karlsen, Tom H.; Franke, Andre; Melum, Espen; Kaser, Arthur; Hov, Johannes Roksund; Balschun, Tobias; Lie, Benedicte A.; Bergquist, Annika; Schramm, Christoph; Weismueller, Tobias J.; Gotthardt, Daniel; Rust, Christian; Philipp, Eva E. R.; Fritz, Teresa; Henckaerts, Liesbet; Weersma, Rinse K.; Stokkers, Pieter; Ponsioen, Cyriel Y.; Wijmenga, Cisca; Sterneck, Martina; Nothnagel, Michael; Hampe, Jochen; Teufel, Andreas; Runz, Heiko; Rosenstiel, Philip; Stiehl, Adolf; Vermeire, Severine; Beuers, Ulrich; Manns, Michael P.; Schrumpf, Erik; Boberg, Kirsten Muri; Schreiber, Stefan

    2010-01-01

    BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA

  7. Voxelwise genome-wide association study (vGWAS)

    Stein, Jason L; Hua, Xue; Lee, Suh; Ho, April J.; Leow, Alex D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Matthew J. Huentelman; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.

    2010-01-01

    The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each o...

  8. The Relationship Between Eight GWAS-Identified Single-Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

    Bayraktar, Soley; Thompson, Patricia A.; Yoo, Suk-Young; Do, Kim-Anh; Sahin, Aysegul A.; Arun, Banu K; Bondy, Melissa L.; Brewster, Abenaa M.

    2013-01-01

    Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies. This study investigated the association of eight risk SNPs with breast cancer disease-free survival and overall survival rates. Results suggest that two previously identified breast cancer risk susceptibility loci may influence breast cancer prognosis or comorbid conditions associated with overall survival.

  9. Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index

    Minster, Ryan L; Sanders, Jason L; Singh, Jatinder;

    2015-01-01

    BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for......: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular...

  10. qpure: A tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles.

    Sarah Song

    Full Text Available Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001 between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16 between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004 between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.

  11. Application of genome-wide single-nucleotide polymorphism arrays to understanding dog disease and evolution

    Quilez Oliete, Javier

    2012-01-01

    El descobriment d’un gran ventall de SNPs arrel dels projectes de seqüenciació de genomes, juntament amb les ràpides millores en el seu genotipatge a gran escala, van permetre el desenvolupament en moltes espècies animals de xips d’alta densitat de SNPs distribuïts pel genoma. Aquesta tesi presenta dos exemples de l’aplicació dels xips de SNPs per tal d’entendre malaltia i evolució en el gos, la història evolutiva del qual el converteix en un model animal apropiat per al mapatge de caràcters ...

  12. LASSO model selection with post-processing for a genome-wide association study data set

    Motyer Allan J; McKendry Chris; Galbraith Sally; Wilson Susan R

    2011-01-01

    Abstract Model selection procedures for simultaneous analysis of all single-nucleotide polymorphisms in genome-wide association studies are most suitable for making full use of the data for a complex disease study. In this paper we consider a penalized regression using the LASSO procedure and show that post-processing of the penalized-regression results with subsequent stepwise selection may lead to improved identification of causal single-nucleotide polymorphisms.

  13. Genome-wide assessment of the association of rare and common copy number variations to testicular germ cell cancer

    Edsgard, Stefan Daniel; Dalgaard, Marlene Danner; Weinhold, Nils; Wesolowska, Agata; Rajpert-De Meyts, Ewa; Ottesen, Anne Marie; Juul, Anders; Skakkebæk, Niels Erik; Jensen, Thomas Skøt; Gupta, Ramneek; Leffers, Henrik; Brunak, Søren

    2013-01-01

    Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212...

  14. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

    Dahlin, Amber; Litonjua, Augusto; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Tantisira, Kelan G.

    2015-01-01

    Background: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Methods: Using genome-wide genotype and phenotypic data available from American Lung Association -...

  15. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

    Dahlin, Amber; Litonjua, Augusto; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Tantisira, Kelan G.

    2015-01-01

    Background Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Methods Using genome-wide genotype and phenotypic data available from American Lung Association - A...

  16. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M; Bernstein, Leslie; Zheng, Wei; Jennifer J Hu; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Sue A Ingles; Michael F. Press; Deming, Sandra L.; Rodriguez-Gil, Jorge L.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyz...

  17. Single nucleotide variations: biological impact and theoretical interpretation.

    Katsonis, Panagiotis; Koire, Amanda; Wilson, Stephen Joseph; Hsu, Teng-Kuei; Lua, Rhonald C; Wilkins, Angela Dawn; Lichtarge, Olivier

    2014-12-01

    Genome-wide association studies (GWAS) and whole-exome sequencing (WES) generate massive amounts of genomic variant information, and a major challenge is to identify which variations drive disease or contribute to phenotypic traits. Because the majority of known disease-causing mutations are exonic non-synonymous single nucleotide variations (nsSNVs), most studies focus on whether these nsSNVs affect protein function. Computational studies show that the impact of nsSNVs on protein function reflects sequence homology and structural information and predict the impact through statistical methods, machine learning techniques, or models of protein evolution. Here, we review impact prediction methods and discuss their underlying principles, their advantages and limitations, and how they compare to and complement one another. Finally, we present current applications and future directions for these methods in biological research and medical genetics. PMID:25234433

  18. Genome-Wide Association Study of Intelligence: Additive Effects of Novel Brain Expressed Genes

    Loo, Sandra K.; Shtir, Corina; Doyle, Alysa E.; Mick, Eric; McGough, James J.; McCracken, James; Biederman, Joseph; Smalley, Susan L.; Cantor, Rita M.; Faraone, Stephen V.; Nelson, Stanley F.

    2012-01-01

    Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally…

  19. A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia

    Need, Anna C.; Ge, Dongliang; Weale, Michael E.; Maia, Jessica; Feng, Sheng; Heinzen, Erin L.; Shianna, Kevin V; Yoon, Woohyun; Kasperaviciute, Dalia; Gennarelli, Massimo; Strittmatter, Warren J.; Bonvicini, Cristian; Rossi, Giuseppe; Jayathilake, Karu; Cola, Philip A.

    2009-01-01

    We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a s...

  20. A genome-wide investigation of SNPs and CNVs in schizophrenia

    Need, A.; Ge, D.; Weale, M; Maia, J.; Feng, S.; Heinzen, E; Shianna, K; Yoon, W.; Kasperavičiūtė, D.; M. GENNARELLI; Strittmatter, W; Bonvicini, C.; Rossi, G; Jayathilake, K.; De Cola, P.

    2009-01-01

    We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a s...

  1. Evaluation of published single nucleotide polymorphisms associated with acute GVHD.

    Chien, Jason W; Zhang, Xinyi Cindy; Fan, Wenhong; Wang, Hongwei; Zhao, Lue Ping; Martin, Paul J; Storer, Barry E; Boeckh, Michael; Warren, Edus H; Hansen, John A

    2012-05-31

    Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed single-nucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P = .011) and recessive (adjusted P = .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P = .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies. PMID:22282500

  2. Modelling the contribution of family history and variation in single nucleotide polymorphisms to risk of schizophrenia

    Agerbo, Esben; Mortensen, Preben Bo; Wiuf, Carsten;

    2012-01-01

    Epidemiological studies indicate that having any family member with schizophrenia increases the risk of schizophrenia in the probands. However, genome-wide association studies (GWAS) have accounted for little of this variation. The aim of this study was to use a population-based sample to explore...... the influence of single-nucleotide polymorphisms (SNPs) on the excess schizophrenia risk in offspring of parents with a psychotic, bipolar affective or other psychiatric disorder....

  3. A Monte Carlo test of linkage disequilibrium for single nucleotide polymorphisms

    Xu, Hongyan; George, Varghese

    2011-01-01

    Background Genetic association studies, especially genome-wide studies, make use of linkage disequilibrium(LD) information between single nucleotide polymorphisms (SNPs). LD is also used for studying genome structure and has been valuable for evolutionary studies. The strength of LD is commonly measured by r 2, a statistic closely related to the Pearson's χ 2 statistic. However, the computation and testing of linkage disequilibrium using r 2 requires known haplotype counts of the SNP pair, wh...

  4. Validation study of candidate single nucleotide polymorphisms associated with left ventricular hypertrophy in the Korean population

    Park, Jin-Kyu; Kim, Mi Kyung; Choi, Bo Youl; Jung, Yusun; Song, Kyuyoung; Kim, Yu Mi; Shin, Jinho

    2015-01-01

    Background Left ventricular hypertrophy (LVH) is a valid predictor for cardiovascular mortality and morbidity regardless of age, gender, and race. The HyperGEN study conducted a genome-wide association study and identified twelve single nucleotide polymorphisms (SNPs) associated with LVH. The aim of this study was to validate these candidate SNPs in the Korean population. Methods Among 1637 individuals from the Korean Multi-Rural Communities Cohort Study (MRCohort) of the Korean Genome Epidem...

  5. Genome-wide patterns of nucleotide polymorphism in domesticated rice

    Caicedo, Ana L; Williamson, Scott H; Hernandez, Ryan D;

    2007-01-01

    Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments......, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models...... plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that...

  6. Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

    Krintel, Sophine B; Palermo, Giuseppe; Johansen, Julia S;

    2012-01-01

    Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the...

  7. Use of longitudinal data in genetic studies in the genome-wide association studies era: summary of Group 14.

    Kerner, Berit; North, Kari E; Fallin, M Daniele

    2009-01-01

    Participants analyzed actual and simulated longitudinal data from the Framingham Heart Study for various metabolic and cardiovascular traits. The genetic information incorporated into these investigations ranged from selected single-nucleotide polymorphisms to genome-wide association arrays. Genotypes were incorporated using a broad range of methodological approaches including conditional logistic regression, linear mixed models, generalized estimating equations, linear growth curve estimation, growth modeling, growth mixture modeling, population attributable risk fraction based on survival functions under the proportional hazards models, and multivariate adaptive splines for the analysis of longitudinal data. The specific scientific questions addressed by these different approaches also varied, ranging from a more precise definition of the phenotype, bias reduction in control selection, estimation of effect sizes and genotype associated risk, to direct incorporation of genetic data into longitudinal modeling approaches and the exploration of population heterogeneity with regard to longitudinal trajectories. The group reached several overall conclusions: (1) The additional information provided by longitudinal data may be useful in genetic analyses. (2) The precision of the phenotype definition as well as control selection in nested designs may be improved, especially if traits demonstrate a trend over time or have strong age-of-onset effects. (3) Analyzing genetic data stratified for high-risk subgroups defined by a unique development over time could be useful for the detection of rare mutations in common multifactorial diseases. (4) Estimation of the population impact of genomic risk variants could be more precise. The challenges and computational complexity demanded by genome-wide single-nucleotide polymorphism data were also discussed. PMID:19924713

  8. Single nucleotide polymorphisms in clinics: Fantasy or reality for cancer?

    Srinivasan, Srilakshmi; Clements, Judith A; Batra, Jyotsna

    2016-02-01

    Single nucleotide polymorphisms (SNPs) have been classically used for dissecting various human complex disorders using candidate gene studies. During the last decade, large scale SNP analysis, i.e. genome-wide association studies (GWAS) have provided an agnostic approach to identify possible genetic loci associated with heterogeneous disease such as cancer susceptibility, prognosis of survival or drug response. Further, the advent of new technologies, including microarray-based genotyping as well as high throughput next generation sequencing has opened new avenues for SNPs to be used in clinical practice. It is speculated that the utility of SNPs to understand the mechanisms, biology of variable drug response and ultimately treatment individualization based on the individual's genome composition will be indispensable in the near future. In the current review, we discuss the advantages and disadvantages of the clinical utility of genetic variants in disease risk-prediction, prognosis, clinical outcome and pharmacogenomics. The lessons and challenges for the utility of SNP-based biomarkers are also discussed, including the need for additional functional validation studies. PMID:26398894

  9. Genome-wide SNP discovery in walnut with an AGSNP pipeline updated for SNP discovery in allogamous organisms

    Background A genome-wide set of single nucleotide polymorphisms (SNPs) is a valuable resource in genetic research and breeding and is usually developed by re-sequencing a genome. If a genome sequence is not available, an alternative strategy must be used. We previously reported the development of a ...

  10. Incorporating group correlations in genome-wide association studies using smoothed group Lasso

    Liu, Jin; Huang, Jian; Ma, Shuangge; Wang, Kai

    2012-01-01

    In genome-wide association studies, penalization is an important approach for identifying genetic markers associated with disease. Motivated by the fact that there exists natural grouping structure in single nucleotide polymorphisms and, more importantly, such groups are correlated, we propose a new penalization method for group variable selection which can properly accommodate the correlation between adjacent groups. This method is based on a combination of the group Lasso penalty and a quad...

  11. A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men

    Zabaneh, Delilah; Balding, David J.

    2010-01-01

    We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits:...

  12. A genome-wide association study of body mass index across early life and childhood

    Nicole M Warrington; Howe, Laura D; Paternoster, Lavinia; Kaakinen, Marika; Herrala, Sauli; Huikari, Ville; Wu, Yan Yan; Kemp, John P.; Timpson, Nicholas J.; Pourcain, Beate St; Davey Smith, George; Tilling, Kate; Jarvelin, Marjo-Riitta; Pennell, Craig E.; Evans, David M.

    2015-01-01

    Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood. Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Ra...

  13. A genome-wide association study of body mass index across early life and childhood

    Warrington, N.; Howe, L; Paternoster, L.; Kaakinen, M.; Herrala, S. (Sauli); Huikari, V.; Wu, Y.; Kemp, J.; Timpson, N.; St Pourcain, B.; Smith, G.; Tilling, K; Jarvelin, M; Pennell, C; Evans, D

    2015-01-01

    Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood. Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Ra...

  14. Genome-wide association scan for five major dimensions of personality

    Terracciano, Antonio; Sanna, Serena; Uda, Manuela; Deiana, Barbara; Usala, Gianluca; Busonero, Fabio; Maschio, Andrea; Scally, Matthew; Patriciu, Nicholas; Chen, Wei-Min; Distel, Marijn A.; Slagboom, Eline P.; Boomsma, Dorret I.; Villafuerte, Sandra; Śliwerska, Elżbieta

    2008-01-01

    Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders, and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome wide association (GWA) scan of 3,972 individuals from a genetically isolated population within Sardinia, Italy. Based on analyses of 362,129 single nucleotide polymorphisms (SNPs) we found several strong sig...

  15. Genome wide association study identifies KCNMA1 contributing to human obesity

    Jiao, Hong; Arner, Peter; Hoffstedt, Johan;

    2011-01-01

    Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population....... Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity....

  16. Analysis of genome-wide association data by large-scale Bayesian logistic regression

    Wang Yuanjia; Sha Nanshi; Fang Yixin

    2009-01-01

    Abstract Single-locus analysis is often used to analyze genome-wide association (GWA) data, but such analysis is subject to severe multiple comparisons adjustment. Multivariate logistic regression is proposed to fit a multi-locus model for case-control data. However, when the sample size is much smaller than the number of single-nucleotide polymorphisms (SNPs) or when correlation among SNPs is high, traditional multivariate logistic regression breaks down. To accommodate the scale of data fro...

  17. Comparison of Genome Wide Variation between Malawians and African Ancestry HapMap Populations

    Joubert, Bonnie R.; North, Kari E.; Wang, Yunfei; Mwapasa, Victor; Franceschini, Nora; Meshnick, Steven R; Lange, Ethan M.

    2010-01-01

    Understanding genetic variation between populations is important because it affects the portability of human genome wide analytical methods. We compared genetic variation and substructure between Malawians and other African and non-African HapMap populations. Allele frequencies and adjacent linkage disequilibrium (LD) were measured for 617,715 single nucleotide polymorphisms (SNPs) across subject genomes. Allele frequencies in the Malawian population (N = 226) were highly correlated with alle...

  18. Genome Wide Sampling Sequencing for SNP Genotyping: Methods, Challenges and Future Development

    Jiang, Zhihua; Wang, Hongyang; Michal, Jennifer J.; Zhou, Xiang; Liu, Bang; Woods, Leah C. Solberg; Fuchs, Rita A.

    2016-01-01

    Genetic polymorphisms, particularly single nucleotide polymorphisms (SNPs), have been widely used to advance quantitative, functional and evolutionary genomics. Ideally, all genetic variants among individuals should be discovered when next generation sequencing (NGS) technologies and platforms are used for whole genome sequencing or resequencing. In order to improve the cost-effectiveness of the process, however, the research community has mainly focused on developing genome-wide sampling seq...

  19. Genome-wide association study of serum selenium concentrations

    Gong, Jian; Hsu, Li; Harrison, Tabitha;

    2013-01-01

    Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this...... hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We...... tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0...

  20. Comparing gene set analysis methods on single-nucleotide polymorphism data from Genetic Analysis Workshop 16

    Tintle, Nathan L; Borchers, Bryce; Brown, Marshall; Bekmetjev, Airat

    2009-01-01

    Recently, gene set analysis (GSA) has been extended from use on gene expression data to use on single-nucleotide polymorphism (SNP) data in genome-wide association studies. When GSA has been demonstrated on SNP data, two popular statistics from gene expression data analysis (gene set enrichment analysis [GSEA] and Fisher's exact test [FET]) have been used. However, GSEA and FET have shown a lack of power and robustness in the analysis of gene expression data. The purpose of this work is to in...

  1. Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals

    Huang, August Y.; Xu, Xiaojing; Ye, Adam Y.; Wu, Qixi; Yan, Linlin; Zhao, Boxun; Yang, Xiaoxu; He, Yao; Wang, Sheng; Zhang, Zheng; Gu, Bowen; Han-qing ZHAO; Wang, Meng; Gao, Hua; Gao, Ge

    2014-01-01

    Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of eff...

  2. Associations of Six Single Nucleotide Polymorphisms in Obesity-Related Genes With BMI and Risk of Obesity in Chinese Children

    Wu, Lijun; Xi, Bo; Zhang, Meixian; SHEN, Yue; Zhao, Xiaoyuan; Cheng, Hong; Hou, Dongqing; Sun, Dandan; Ott, Jurg; Wang, Xingyu; Mi, Jie

    2010-01-01

    OBJECTIVE Childhood obesity strongly predisposes to some adult diseases. Recently, genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with BMI and obesity. The associations of those SNPs with BMI and obesity among other ethnicities are not fully described, especially in children. Among those previously identified SNPs, we selected six (rs7138803, rs1805081, rs6499640, rs17782313, rs6265, and rs10938397, in or near obesity-...

  3. The genetic diversity and structure of indica rice in China as detected by single nucleotide polymorphism analysis

    Xu, Qun; Yuan, Xiaoping; Wang, Shan; Feng, Yue; Yu, Hanyong; Wang, Yiping; Yang, Yaolong; Wei, Xinghua; Li, Ximing

    2016-01-01

    Background Rice (Oryza sativa L.) is the staple food of more than half of the world’s population. The identification of genetic diversity in local varieties of rice compared with that of improved or introduced varieties is important in breeding elite varieties for sustainable agriculture. Array-based single nucleotide polymorphism (SNP) detection is a useful technique for such studies and breeding applications. Results We developed a 5291-SNP genome-wide array and used it to genotype 471 indi...

  4. Analysis of the genotype of diacylglycerol kinase delta single-nucleotide polymorphisms in Parkinson disease in the Han Chinese population

    Wei Song; Yong Ping Chen; Rui Huang; Ke Chen; Ping Lei Pan; Jianpeng Li; Yuan Yang; Hui-Fang Shang

    2012-01-01

    Numerous Single-Nucleotide Polymorphisms (SNPs) of the Diacylglycerol Kinase Delta (DGKD) isoform 1 gene have been associated with Parkinson Disease (PD) in the genome-wide association studies of Caucasian population. This association has not been proven in the Han Chinese PD patients. This study included 376 unrelated Han Chinese PD patients from West China and 273 unrelated healthy controls from the same region. Five SNPs (rs2971859, rs1550532, rs2305539, rs2034762, and rs2242102) were geno...

  5. Genome-Wide Association Study of Antiphospholipid Antibodies

    M. Ilyas Kamboh

    2013-01-01

    Full Text Available Background. The persistent presence of antiphospholipid antibodies (APA may lead to the development of primary or secondary antiphospholipid syndrome. Although the genetic basis of APA has been suggested, the identity of the underlying genes is largely unknown. In this study, we have performed a genome-wide association study (GWAS in an effort to identify susceptibility loci/genes for three main APA: anticardiolipin antibodies (ACL, lupus anticoagulant (LAC, and anti-β2 glycoprotein I antibodies (anti-β2GPI. Methods. DNA samples were genotyped using the Affymetrix 6.0 array containing 906,600 single-nucleotide polymorphisms (SNPs. Association of SNPs with the antibody status (positive/negative was tested using logistic regression under the additive model. Results. We have identified a number of suggestive novel loci with Pgenome-wide significance, many of the suggestive loci are potential candidates for the production of APA. We have replicated the previously reported associations of HLA genes and APOH with APA but these were not the top loci. Conclusions. We have identified a number of suggestive novel loci for APA that will stimulate follow-up studies in independent and larger samples to replicate our findings.

  6. Genome-wide patterns of nucleotide polymorphism in domesticated rice.

    Ana L Caicedo

    2007-09-01

    Full Text Available Domesticated Asian rice (Oryza sativa is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i selectively neutral population bottleneck model, (ii bottleneck plus migration model, (iii multiple selective sweeps model, and (iv bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation.

  7. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    Børglum, A D; Demontis, D; Grove, J;

    2014-01-01

    Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals...... born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and...... region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection...

  8. Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate

    Beaty, Terri H; Ruczinski, Ingo; Murray, Jeffrey C;

    2011-01-01

    separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when......Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international...... consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a...

  9. Genome-wide association study of obsessive-compulsive disorder.

    Stewart, S E; Yu, D; Scharf, J M; Neale, B M; Fagerness, J A; Mathews, C A; Arnold, P D; Evans, P D; Gamazon, E R; Davis, L K; Osiecki, L; McGrath, L; Haddad, S; Crane, J; Hezel, D; Illman, C; Mayerfeld, C; Konkashbaev, A; Liu, C; Pluzhnikov, A; Tikhomirov, A; Edlund, C K; Rauch, S L; Moessner, R; Falkai, P; Maier, W; Ruhrmann, S; Grabe, H-J; Lennertz, L; Wagner, M; Bellodi, L; Cavallini, M C; Richter, M A; Cook, E H; Kennedy, J L; Rosenberg, D; Stein, D J; Hemmings, S M J; Lochner, C; Azzam, A; Chavira, D A; Fournier, E; Garrido, H; Sheppard, B; Umaña, P; Murphy, D L; Wendland, J R; Veenstra-VanderWeele, J; Denys, D; Blom, R; Deforce, D; Van Nieuwerburgh, F; Westenberg, H G M; Walitza, S; Egberts, K; Renner, T; Miguel, E C; Cappi, C; Hounie, A G; Conceição do Rosário, M; Sampaio, A S; Vallada, H; Nicolini, H; Lanzagorta, N; Camarena, B; Delorme, R; Leboyer, M; Pato, C N; Pato, M T; Voyiaziakis, E; Heutink, P; Cath, D C; Posthuma, D; Smit, J H; Samuels, J; Bienvenu, O J; Cullen, B; Fyer, A J; Grados, M A; Greenberg, B D; McCracken, J T; Riddle, M A; Wang, Y; Coric, V; Leckman, J F; Bloch, M; Pittenger, C; Eapen, V; Black, D W; Ophoff, R A; Strengman, E; Cusi, D; Turiel, M; Frau, F; Macciardi, F; Gibbs, J R; Cookson, M R; Singleton, A; Hardy, J; Crenshaw, A T; Parkin, M A; Mirel, D B; Conti, D V; Purcell, S; Nestadt, G; Hanna, G L; Jenike, M A; Knowles, J A; Cox, N; Pauls, D L

    2013-07-01

    Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (Pquantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. PMID:22889921

  10. Targeted and genome-wide sequencing reveal single nucleotide variations impacting specificity of Cas9 in human stem cells

    Yang, Luhan; Grishin, Dennis; Wang, Gang; Aach, John; Zhang, Cheng-Zhong; Chari, Raj; Homsy, Jason; Cai, Xuyu; ZHAO, YUE; Fan, Jian-Bing; Seidman, Christine; Seidman, Jonathan; Pu, William; Church, George

    2014-01-01

    CRISPR/Cas9 has demonstrated a high-efficiency in site-specific gene targeting. However, potential off-target effects of the Cas9 nuclease represent a major safety concern for any therapeutic application. Here, we knock out the Tafazzin gene by CRISPR/Cas9 in human-induced pluripotent stem cells with 54% efficiency. We combine whole-genome sequencing and deep-targeted sequencing to characterise the off-target effects of Cas9 editing. Whole-genome sequencing of Cas9-modified hiPSC clones detec...

  11. Software for tag single nucleotide polymorphism selection

    Stram Daniel O

    2005-06-01

    Full Text Available Abstract This paper reviews the theoretical basis for single nucleotide polymorphism (SNP tagging and considers the use of current software made freely available for this task. A distinction between haplotype block-based and non-block-based approaches yields two classes of procedures. Analysis of two different sets of SNP genotype data from the HapMap is used to judge the practical aspects of using each of the programs considered, as well as to make some general observations about the performance of the programs in finding optimal sets of tagging SNPs. Pairwise R2 methods, while the simplest of those considered, do tend to pick more tagging SNPs than are strictly needed to predict unmeasured (non-tagging SNPs, since a combination of two or more tagging SNPs can form a prediction of SNPs that have no direct (pairwise surrogate. Block-based methods that exploit the linkage disequilibrium structure within haplotype blocks exploit this sort of redundancy, but run a risk of over-fitting if used without some care. A compromise approach which eliminates the need first to analyse block structure, but which still exploits simple relationships between SNPs, appears promising.

  12. Genome Wide Association Analysis Reveals New Production Trait Genes in a Male Duroc Population.

    Kejun Wang

    Full Text Available In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1, seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3, and one for average daily gain (COL27A1. Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection.

  13. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine

    Esserlind, A-L; Christensen, A F; Le, H;

    2013-01-01

    Genetic factors contribute to the aetiology of the prevalent form of migraine without aura (MO) and migraine with typical aura (MTA). Due to the complex inheritance of MO and MTA, the genetic background is still not fully established. In a population-based genome-wide association study by Chasman...... et al. (Nat Genet 2011: 43: 695-698), three common variants were found to confer risk of migraine at a genome-wide significant level (P <5 × 10(-8) ). We aimed to evaluate the top association single nucleotide polymorphisms (SNPs) from the discovery set by Chasman et al. in a primarily clinic...

  14. Empirical Bayes analysis of single nucleotide polymorphisms

    Ickstadt Katja

    2008-03-01

    Full Text Available Abstract Background An important goal of whole-genome studies concerned with single nucleotide polymorphisms (SNPs is the identification of SNPs associated with a covariate of interest such as the case-control status or the type of cancer. Since these studies often comprise the genotypes of hundreds of thousands of SNPs, methods are required that can cope with the corresponding multiple testing problem. For the analysis of gene expression data, approaches such as the empirical Bayes analysis of microarrays have been developed particularly for the detection of genes associated with the response. However, the empirical Bayes analysis of microarrays has only been suggested for binary responses when considering expression values, i.e. continuous predictors. Results In this paper, we propose a modification of this empirical Bayes analysis that can be used to analyze high-dimensional categorical SNP data. This approach along with a generalized version of the original empirical Bayes method are available in the R package siggenes version 1.10.0 and later that can be downloaded from http://www.bioconductor.org. Conclusion As applications to two subsets of the HapMap data show, the empirical Bayes analysis of microarrays cannot only be used to analyze continuous gene expression data, but also be applied to categorical SNP data, where the response is not restricted to be binary. In association studies in which typically several ten to a few hundred SNPs are considered, our approach can furthermore be employed to test interactions of SNPs. Moreover, the posterior probabilities resulting from the empirical Bayes analysis of (prespecified interactions/genotypes can also be used to quantify the importance of these interactions.

  15. Genome-wide scan for visceral leishmaniasis in mixed-breed dogs identifies candidate genes involved in T helper cells and macrophage signaling

    We conducted a genome-wide scan for visceral leishmaniasis in mixed-breed dogs from a highly endemic area in Brazil using 149,648 single nucleotide polymorphism (SNP) markers genotyped in 20 cases and 28 controls. Using a mixed model approach, we found two candidate loci on canine autosomes 1 and 2....

  16. Whole-genome association analysis to identify markers associated with recombination rates using single-nucleotide polymorphisms and microsatellites.

    Huang, Song; Wang, Shuang; Liu, Nianjun; Chen, Liang; Oh, Cheongeun; Zhao, Hongyu

    2005-01-01

    Recombination during meiosis is one of the most important biological processes, and the level of recombination rates for a given individual is under genetic control. In this study, we conducted genome-wide association studies to identify chromosomal regions associated with recombination rates. We analyzed genotype data collected on the pedigrees in the Collaborative Study on the Genetics on Alcoholism data provided by Genetic Analysis Workshop 14. A total of 315 microsatellites and 10,081 single-nucleotide polymorphisms from Affymetrix on 22 autosomal chromosomes were used in our association analysis. Genome-wide gender-specific recombination counts for family founders were inferred first and association analysis was performed using multiple linear regressions. We used the positive false discovery rate (pFDR) to account for multiple comparisons in the two genome-wide scans. Eight regions showed some evidence of association with recombination counts based on the single-nucleotide polymorphism analysis after adjusting for multiple comparisons. However, no region was found to be significant using microsatellites. PMID:16451663

  17. Family-based Genome-wide Association Study of Frontal Theta Oscillations Identifies Potassium Channel Gene KCNJ6

    Kang, Sun J.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Wetherill, Leah; Hinrichs, Tony; Almasy, Laura; Brooks, Andy; Chorlian, David B.; Dick, Danielle; Hesselbrock, Victor; Kramer, John; Kuperman, Sam; Nurnberger, John; Rice, John,

    2012-01-01

    Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 1...

  18. Genome Wide Association Study and Follow-Up Analysis of Adiposity Traits in Hispanic-Americans: the IRAS Family Study

    Norris, Jill M.; Langefeld, Carl D.; Talbert, Matthew E.; Wing, Maria R; Haritunians, Talin; Fingerlin, Tasha E.; Hanley, Anthony J. G.; Ziegler, Julie T.; Taylor, Kent D.; Haffner, Steven M.; Chen, Yii-Der I.; Donald W Bowden; Wagenknecht, Lynne E.

    2009-01-01

    We investigated candidate genomic regions associated with computed tomography (CT)-derived measures of adiposity in Hispanic from the IRAS Family Study. In 1190 Hispanic individuals from 92 families from the San Luis Valley, CO and San Antonio, TX, we measured CT-derived visceral adipose tissue (VAT); subcutaneous adipose tissue (SAT); and visceral: subcutaneous ratio (VSR). A genome-wide association study (GWAS) was completed using the Illumina HumanHap 300 BeadChip (~317K single nucleotide ...

  19. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

    Cupples, L. Adrienne; D'Agostino, Ralph B.; Hwang, Shih-Jen; Ingellson, Erik; Liu, Chunyu; Murabito, Joanne M.; Polak, Joseph F.; Wolf, Philip A.; Demissie, Serkalem; O'Donnell, Christopher Joseph; Fox, Caroline; Hoffmann, Udo

    2007-01-01

    Introduction: Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study. Methods: Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multiva...

  20. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

    Hwang Shih-Jen; Hoffmann Udo; Fox Caroline S; D'Agostino Ralph B; Cupples L Adrienne; O'Donnell Christopher J; Ingellson Erik; Liu Chunyu; Murabito Joanne M; Polak Joseph F; Wolf Philip A; Demissie Serkalem

    2007-01-01

    Abstract Introduction Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study. Methods Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and ...

  1. A Validated Genome Wide Association Study to Breed Cattle Adapted to an Environment Altered by Climate Change

    Hayes, Ben J; Bowman, Phil J; Chamberlain, Amanda J.; Savin, Keith; Van Tassell, Curt P; Sonstegard, Tad S.; Goddard, Mike E.

    2009-01-01

    Continued production of food in areas predicted to be most affected by climate change, such as dairy farming regions of Australia, will be a major challenge in coming decades. Along with rising temperatures and water shortages, scarcity of inputs such as high energy feeds is predicted. With the motivation of selecting cattle adapted to these changing environments, we conducted a genome wide association study to detect DNA markers (single nucleotide polymorphisms) associated with the sensitivi...

  2. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

    Sun, Qi; Cornelis, Marilyn C; Kraft, Peter; Qi, Lu; van Dam, Rob M.; Girman, Cynthia J.; Cathy C Laurie; Mirel, Daniel B.; Gong, Huizi; Sheu, Chau-Chyun; Christiani, David C.; Hunter, David J.; Mantzoros, Christos S.; Hu, Frank B.

    2010-01-01

    Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < ...

  3. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

    Li, Donghui; Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-De-Mesquita, H Bas; Fuchs, Charles S; Gallinger, Steven; Gross, Myron

    2012-01-01

    Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic...

  4. An efficient weighted tag SNP-set analytical method in genome-wide association studies

    Yan, Bin; Wang, Shudong; Jia, Huaqian; Liu, Xing; Wang, Xinzeng

    2015-01-01

    Background Single-nucleotide polymorphism (SNP)-set analysis in Genome-wide association studies (GWAS) has emerged as a research hotspot for identifying genetic variants associated with disease susceptibility. But most existing methods of SNP-set analysis are affected by the quality of SNP-set, and poor quality of SNP-set can lead to low power in GWAS. Results In this research, we propose an efficient weighted tag-SNP-set analytical method to detect the disease associations. In our method, we...

  5. Genome wide association study on early puberty in Bos indicus.

    Nascimento, A V; Matos, M C; Seno, L O; Romero, A R S; Garcia, J F; Grisolia, A B

    2016-01-01

    The aim of this study was to evaluate a genome wide association study (GWAS) approach to identify single nucleotide polymorphisms (SNPs) associated with fertility traits (early puberty) in Nellore cattle (Bos indicus). Fifty-five Nellore cows were selected from a herd monitored for early puberty onset (positive pregnancy at 18 months of age). Extremes of this phenotype were selected; 30 and 25 individuals were pregnant and non-pregnant, respectively, at that age. DNA samples were genotyped using a high-density SNP chip (>777.000 SNP). GWAS using a case-control strategy highlighted a number of significant markers based on their proximity with the Bonferroni correction line. Results indicated that chromosomes 5, 6, 9, 10, and 22 were associated with the traits of interest. The most significant SNPs on these chromosomes were rs133039577, rs110013280, rs134702839, rs109551605, and rs41639155. Candidate genes, as well as quantitative trait loci (QTL) previously reported in the Ensembl and Cattle QTLdb databases, were further investigated. Analysis of the regions close to the SNP on chromosomes 9 and 10 revealed that four QTL had been previously classified under the reproduction category. In conclusion, we have identified SNPs in close proximity to genes associated with reproductive traits. Moreover, U6 spliceosomal RNA was present on three different chromosomes, which is possibly associated with age at first calving, suggesting that it might be a strong candidate for future studies. PMID:26909970

  6. Genome-Wide Association Studies of the Human Gut Microbiota.

    Emily R Davenport

    Full Text Available The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both. These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%. For example, we identified an association between a taxon known to affect obesity (genus Akkermansia and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7. Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut.

  7. Genome-Wide Association Study of Serum Selenium Concentrations

    Ulrike Peters

    2013-05-01

    Full Text Available Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening and the Women’s Health Initiative (WHI. We tested association between 2,474,333 single nucleotide polymorphisms (SNPs and serum selenium concentrations using linear regression models. In the first stage (PLCO 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003 in the second stage (WHI. Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11 and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI. Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

  8. Psoriasis prediction from genome-wide SNP profiles

    Fang Xiangzhong

    2011-01-01

    Full Text Available Abstract Background With the availability of large-scale genome-wide association study (GWAS data, choosing an optimal set of SNPs for disease susceptibility prediction is a challenging task. This study aimed to use single nucleotide polymorphisms (SNPs to predict psoriasis from searching GWAS data. Methods Totally we had 2,798 samples and 451,724 SNPs. Process for searching a set of SNPs to predict susceptibility for psoriasis consisted of two steps. The first one was to search top 1,000 SNPs with high accuracy for prediction of psoriasis from GWAS dataset. The second one was to search for an optimal SNP subset for predicting psoriasis. The sequential information bottleneck (sIB method was compared with classical linear discriminant analysis(LDA for classification performance. Results The best test harmonic mean of sensitivity and specificity for predicting psoriasis by sIB was 0.674(95% CI: 0.650-0.698, while only 0.520(95% CI: 0.472-0.524 was reported for predicting disease by LDA. Our results indicate that the new classifier sIB performs better than LDA in the study. Conclusions The fact that a small set of SNPs can predict disease status with average accuracy of 68% makes it possible to use SNP data for psoriasis prediction.

  9. A genome-wide scan for breast cancer risk haplotypes among African American women.

    Chi Song

    Full Text Available Genome-wide association studies (GWAS simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645, thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

  10. Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease.

    Evangelos Evangelou

    Full Text Available BACKGROUND: Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. METHODOLOGY/PRINCIPAL FINDINGS: Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1 enhancement of replication data and (2 enhancement of first-stage data, and then, we also considered (3 joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2 = 0, 0 and 15%, respectively. Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets. CONCLUSIONS/SIGNIFICANCE: Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.

  11. Patterns of Genome-Wide VDR Locations

    Tuoresmäki, Pauli; Väisänen, Sami; Neme, Antonio; Heikkinen, Sami; Carlberg, Carsten

    2014-01-01

    The genome-wide analysis of the binding sites of the transcription factor vitamin D receptor (VDR) is essential for a global appreciation the physiological impact of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Genome-wide analysis of lipopolysaccharide (LPS)-polarized THP-1 human monocytic leukemia cells via chromatin immunoprecipitation sequencing (ChIP-seq) resulted in 1,318 high-confidence VDR binding sites, of which 789 and 364 occurred uniquely with and without 1,25(OH)2...

  12. Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries

    Baurley, James W.; Edlund, Christopher K.; Pardamean, Carissa I.; Conti, David V.; Krasnow, Ruth; Javitz, Harold S.; Hops, Hyman; Swan, Gary E.; Benowitz, Neal L.

    2016-01-01

    Introduction: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3′-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. Methods: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. Results: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values genome-wide association of CYP2A6 single nucleotide and insertion–deletion polymorphisms. We identify three regions of genome-wide significance: proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism

  13. Evidence for single nucleotide polymorphisms and their association with bipolar disorder

    Szczepankiewicz A

    2013-10-01

    Full Text Available Aleksandra Szczepankiewicz1,21Laboratory of Molecular and Cell Biology, 2Department of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, PolandAbstract: Bipolar disorder (BD is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs. Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1] to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3] replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.Keywords: candidate gene, genome-wide association study, SLC6A4, BDNF, DAOA, DTNBP1, NRG1, DISC1

  14. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax.

    Sousa, Inês; Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura E Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís; Feijó, Salvato; Oliveira, Sofia A

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  15. Mosaic paternal genome-wide uniparental isodisomy with down syndrome.

    Darcy, Diana; Atwal, Paldeep Singh; Angell, Cathy; Gadi, Inder; Wallerstein, Robert

    2015-10-01

    We report on a 6-month-old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome-wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith-Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no specific features of AS. Clinical features of this patient include: dysmorphic features consistent with trisomy 21, tetralogy of Fallot, hemihypertrophy, swirled skin hyperpigmentation, hepatoblastoma, and Wilms tumor. Her karyotype is 47,XX,+21[19]/46,XX[4], and microarray results suggest that the cell line with trisomy 21 is biparentally inherited and represents 40-50% of the genomic material in the tested specimen. The difference in the level of cytogenetically detected mosaicism versus the level of mosaicism observed via microarray analysis is likely caused by differences in the test methodologies. While a handful of cases of mosaic paternal GWUPiD have been reported, this patient is the only reported case that also involves trisomy 21. Other GWUPiD patients have presented with features associated with multiple imprinted regions, as does our patient. PMID:26219535

  16. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma.

    Amber Dahlin

    Full Text Available Genome-wide association study (GWAS is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs. Leukotriene receptor antagonists (LTRAs are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09, and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

  17. A Laboratory Exercise for Genotyping Two Human Single Nucleotide Polymorphisms

    Fernando, James; Carlson, Bradley; LeBard, Timothy; McCarthy, Michael; Umali, Finianne; Ashton, Bryce; Rose, Ferrill F., Jr.

    2016-01-01

    The dramatic decrease in the cost of sequencing a human genome is leading to an era in which a wide range of students will benefit from having an understanding of human genetic variation. Since over 90% of sequence variation between humans is in the form of single nucleotide polymorphisms (SNPs), a laboratory exercise has been devised in order to…

  18. Single nucleotide polymorphism (SNP) detection on a magnetoresistive sensor

    Rizzi, Giovanni; Østerberg, Frederik Westergaard; Dufva, Martin;

    2013-01-01

    We present a magnetoresistive sensor platform for hybridization assays and demonstrate its applicability on single nucleotide polymorphism (SNP) genotyping. The sensor relies on anisotropic magnetoresistance in a new geometry with a local negative reference and uses the magnetic field from the...

  19. Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder

    Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H.

    2012-01-01

    Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs)…

  20. Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies

    Abnet, Christian C.; Wang, Zhaoming; SONG, XIN; Hu, Nan; Zhou, Fu-You; Freedman, Neal D.; Li, Xue-Min; Yu, Kai; Shu, Xiao-Ou; Yuan, Jian-Min; Zheng, Wei; Dawsey, Sanford M.; Liao, Linda M.; Lee, Maxwell P.; DING, Ti

    2012-01-01

    Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) o...

  1. Computational Analysis of Single Nucleotide Polymorphisms Associated with Altered Drug Responsiveness in Type 2 Diabetes

    Valerio Costa

    2016-06-01

    Full Text Available Type 2 diabetes (T2D is one of the most frequent mortality causes in western countries, with rapidly increasing prevalence. Anti-diabetic drugs are the first therapeutic approach, although many patients develop drug resistance. Most drug responsiveness variability can be explained by genetic causes. Inter-individual variability is principally due to single nucleotide polymorphisms, and differential drug responsiveness has been correlated to alteration in genes involved in drug metabolism (CYP2C9 or insulin signaling (IRS1, ABCC8, KCNJ11 and PPARG. However, most genome-wide association studies did not provide clues about the contribution of DNA variations to impaired drug responsiveness. Thus, characterizing T2D drug responsiveness variants is needed to guide clinicians toward tailored therapeutic approaches. Here, we extensively investigated polymorphisms associated with altered drug response in T2D, predicting their effects in silico. Combining different computational approaches, we focused on the expression pattern of genes correlated to drug resistance and inferred evolutionary conservation of polymorphic residues, computationally predicting the biochemical properties of polymorphic proteins. Using RNA-Sequencing followed by targeted validation, we identified and experimentally confirmed that two nucleotide variations in the CAPN10 gene—currently annotated as intronic—fall within two new transcripts in this locus. Additionally, we found that a Single Nucleotide Polymorphism (SNP, currently reported as intergenic, maps to the intron of a new transcript, harboring CAPN10 and GPR35 genes, which undergoes non-sense mediated decay. Finally, we analyzed variants that fall into non-coding regulatory regions of yet underestimated functional significance, predicting that some of them can potentially affect gene expression and/or post-transcriptional regulation of mRNAs affecting the splicing.

  2. Comprehensive identification of single nucleotide polymorphisms associated with beta-lactam resistance within pneumococcal mosaic genes.

    Claire Chewapreecha

    2014-08-01

    Full Text Available Traditional genetic association studies are very difficult in bacteria, as the generally limited recombination leads to large linked haplotype blocks, confounding the identification of causative variants. Beta-lactam antibiotic resistance in Streptococcus pneumoniae arises readily as the bacteria can quickly incorporate DNA fragments encompassing variants that make the transformed strains resistant. However, the causative mutations themselves are embedded within larger recombined blocks, and previous studies have only analysed a limited number of isolates, leading to the description of "mosaic genes" as being responsible for resistance. By comparing a large number of genomes of beta-lactam susceptible and non-susceptible strains, the high frequency of recombination should break up these haplotype blocks and allow the use of genetic association approaches to identify individual causative variants. Here, we performed a genome-wide association study to identify single nucleotide polymorphisms (SNPs and indels that could confer beta-lactam non-susceptibility using 3,085 Thai and 616 USA pneumococcal isolates as independent datasets for the variant discovery. The large sample sizes allowed us to narrow the source of beta-lactam non-susceptibility from long recombinant fragments down to much smaller loci comprised of discrete or linked SNPs. While some loci appear to be universal resistance determinants, contributing equally to non-susceptibility for at least two classes of beta-lactam antibiotics, some play a larger role in resistance to particular antibiotics. All of the identified loci have a highly non-uniform distribution in the populations. They are enriched not only in vaccine-targeted, but also non-vaccine-targeted lineages, which may raise clinical concerns. Identification of single nucleotide polymorphisms underlying resistance will be essential for future use of genome sequencing to predict antibiotic sensitivity in clinical microbiology.

  3. Genome-wide search for gene-gene interactions in colorectal cancer.

    Shuo Jiao

    Full Text Available Genome-wide association studies (GWAS have successfully identified a number of single-nucleotide polymorphisms (SNPs associated with colorectal cancer (CRC risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI. With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4. For the known locus rs10795668 (10p14, we found an interacting SNP rs367615 (5q21 with replication p = 0.01 and combined p = 4.19×10(-8. Among the top marginal SNPs after LD pruning (n = 163, we identified an interaction between rs1571218 (20p12.3 and rs10879357 (12q21.1 (nominal combined p = 2.51×10(-6; Bonferroni adjusted p = 0.03. Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

  4. SNP- and haplotype-based genome-wide association studies for growth, carcass, and meat quality traits in a Duroc multigenerational population

    SATO, Shuji; Uemoto, Yoshinobu; Kikuchi, Takashi; EGAWA, Sachiko; Kohira, Kimiko; Saito, Tomomi; Sakuma, Hironori; Miyashita, Satoshi; Arata, Shinji; Kojima, Takatoshi; Suzuki, Keiichi

    2016-01-01

    Background The aim of the present study was to compare the power of single nucleotide polymorphism (SNP)-based genome-wide association study (GWAS) and haplotype-based GWAS for quantitative trait loci (QTL) detection, and to detect novel candidate genes affecting economically important traits in a purebred Duroc population comprising seven-generation pedigree. First, we performed a simulation analysis using real genotype data of this population to compare the power (based on the null hypothes...

  5. Polygenic Transmission and Complex Neuro developmental Network for Attention Deficit Hyperactivity Disorder: Genome-Wide Association Study of Both Common and Rare Variants

    Yang, Li; et al

    2013-01-01

    Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK....

  6. Genome-Wide Association Study Reveals Novel Quantitative Trait Loci Associated with Resistance to Multiple Leaf Spot Diseases of Spring Wheat

    Gurung, Suraj; Mamidi, Sujan; Bonman, J Michael; Xiong, Mai; Brown-Guedira, Gina; Adhikari, Tika B.

    2014-01-01

    Accelerated wheat development and deployment of high-yielding, climate resilient, and disease resistant cultivars can contribute to enhanced food security and sustainable intensification. To facilitate gene discovery, we assembled an association mapping panel of 528 spring wheat landraces of diverse geographic origin for a genome-wide association study (GWAS). All accessions were genotyped using an Illumina Infinium 9K wheat single nucleotide polymorphism (SNP) chip and 4781 polymorphic SNPs ...

  7. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women

    Barnholtz-Sloan, Jill S; Shetty, Priya B; Guan, Xiaowei; Nyante, Sarah J; Luo, Jingchun; Brennan, Donal J.; Millikan, Robert C.

    2010-01-01

    Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry ...

  8. A novel method to identify high order gene-gene interactions in genome-wide association studies: Gene-based MDR

    Oh Sohee; Lee Jaehoon; Kwon Min-Seok; Weir Bruce; Ha Kyooseob; Park Taesung

    2012-01-01

    Abstract Background Because common complex diseases are affected by multiple genes and environmental factors, it is essential to investigate gene-gene and/or gene-environment interactions to understand genetic architecture of complex diseases. After the great success of large scale genome-wide association (GWA) studies using the high density single nucleotide polymorphism (SNP) chips, the study of gene-gene interaction becomes a next challenge. Multifactor dimensionality reduction (MDR) analy...

  9. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Fuchs, Charles S; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D

    2009-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-con...

  10. Lessons and Implications from Genome-Wide Association Studies (GWAS Findings of Blood Cell Phenotypes

    Nathalie Chami

    2014-01-01

    Full Text Available Genome-wide association studies (GWAS have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, large-scale (epigenomic studies and bioinformatic analyses strongly suggest that GWAS hits are not randomly distributed in the genome but rather pinpoint specific biological pathways important for disease development or phenotypic variation. In this review, we focus on GWAS discoveries for the three main blood cell types: red blood cells, white blood cells and platelets. We summarize the knowledge gained from GWAS of these phenotypes and discuss their possible clinical implications for common (e.g., anemia and rare (e.g., myeloproliferative neoplasms human blood-related diseases. Finally, we argue that blood phenotypes are ideal to study the genetics of complex human traits because they are fully amenable to experimental testing.

  11. Genome-wide association study for ovarian cancer susceptibility using pooled DNA

    Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan; Johnatty, Sharon E; Defazio, Anna; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn; Vergotes, Ignace; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Goodman, Marc T; Lurie, Galina; Wilkens, Lynne R; Carney, Michael E; Butzow, Ralf; Nevanlinna, Heli; Heikkinen, Tuomas; Leminen, Arto; Kiemeney, Lambertus A; Massuger, Leon F A G; van Altena, Anne M; Aben, Katja K; Kjaer, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Brooks-Wilson, Angela; Le, Nhu; Cook, Linda; Earp, Madalene; Kelemen, Linda; Easton, Douglas; Pharoah, Paul; Song, Honglin; Tyrer, Jonathan; Ramus, Susan; Menon, Usha; Gentry-Maharaj, Alexandra; Gayther, Simon A; Bandera, Elisa V; Olson, Sara H; Orlow, Irene; Rodriguez-Rodriguez, Lorna; Macgregor, Stuart; Chenevix-Trench, Georgia

    2012-01-01

    Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in...... the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly...... associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for...

  12. Genome-wide association study identifies three novel loci for type 2 diabetes

    Hara, Kazuo; Fujita, Hayato; Johnson, Todd A;

    2014-01-01

    genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases...... (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.......Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly...

  13. A Genome-Wide Perspective on Metabolism

    Rauch, Alexander; Mandrup, Susanne

    2015-01-01

    Mammals have at least 210 histologically diverse cell types (Alberts, Molecular biology of the cell. Garland Science, New York, 2008) and the number would be even higher if functional differences are taken into account. The genome in each of these cell types is differentially programmed to express...... the specific set of genes needed to fulfill the phenotypical requirements of the cell. Furthermore, in each of these cell types, the gene program can be differentially modulated by exposure to external signals such as hormones or nutrients. The basis for the distinct gene programs relies on cell type...... number of technologies that can be used to obtain genome-wide insight into how genomes are reprogrammed during development and in response to specific external signals. By applying such technologies, we have begun to reveal the cross-talk between metabolism and the genome, i.e., how genomes are...

  14. Genome-wide Analysis of Gene Regulation

    Chen, Yun

    cells are capable of regulating their gene expression, so that each cell can only express a particular set of genes yielding limited numbers of proteins with specialized functions. Therefore a rigid control of differential gene expression is necessary for cellular diversity. On the other hand, aberrant...... gene regulation will disrupt the cell’s fundamental processes, which in turn can cause disease. Hence, understanding gene regulation is essential for deciphering the code of life. Along with the development of high throughput sequencing (HTS) technology and the subsequent large-scale data analysis......, genome-wide assays have increased our understanding of gene regulation significantly. This thesis describes the integration and analysis of HTS data across different important aspects of gene regulation. Gene expression can be regulated at different stages when the genetic information is passed from gene...

  15. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13

    Cho, Michael H; Castaldi, Peter J; Wan, Emily S;

    2012-01-01

    The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through......KOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10......(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre...

  16. Genome-wide sequencing reveals two major sub-lineages in the genetically monomorphic pathogen xanthomonas campestris pathovar musacearum.

    Wasukira, Arthur; Tayebwa, Johnbosco; Thwaites, Richard; Paszkiewicz, Konrad; Aritua, Valente; Kubiriba, Jerome; Smith, Julian; Grant, Murray; Studholme, David J

    2012-01-01

    The bacterium Xanthomonas campestris pathovar musacearum (Xcm) is the causal agent of banana Xanthomonas wilt (BXW). This disease has devastated economies based on banana and plantain crops (Musa species) in East Africa. Here we use genome-wide sequencing to discover a set of single-nucleotide polymorphisms (SNPs) among East African isolates of Xcm. These SNPs have potential as molecular markers for phylogeographic studies of the epidemiology and spread of the pathogen. Our analysis reveals two major sub-lineages of the pathogen, suggesting that the current outbreaks of BXW on Musa species in the region may have more than one introductory event, perhaps from Ethiopia. Also, based on comparisons of genome-wide sequence data from multiple isolates of Xcm and multiple strains of X. vasicola pathovar vasculorum, we identify genes specific to Xcm that could be used to specifically detect Xcm by PCR-based methods. PMID:24704974

  17. Single nucleotide polymorphisms of complement component 5 and periodontitis

    L. Chai; Zee, KY; Song, YQ; Leung, WK

    2010-01-01

    BACKGROUND AND OBJECTIVE: Polymorphisms of host defence genes might increase one's risks for periodontitis. This study investigated whether tagging single nucleotide polymorphisms (SNPs) of the gene encoding complement component 5 (C5) are associated with periodontitis in a Hong Kong Chinese population. MATERIAL AND METHODS: Eleven tagging SNPs of 229 patients with at least moderate periodontitis and 207 control subjects without periodontitis were genotyped using an i-plexGOLD MassARRAY mass-...

  18. Utilizing Single Nucleotide Polymorphism Analysis in Determining Parentage of Cattle

    Elbert, Nicole M.

    2013-01-01

    Parentage identification within cattle herds is an important aspect of record keeping. It is essential for accurate registration within a purebred association and decision making for production purposes, such as replacement heifer and sire selection. Methods used to identify parentage have evolved from utilizing blood protein antigens, restriction fragment length polymorphism (RFLP) and microsatellites to the current technology of analyzing DNA profiles for differing single nucleotide polymor...

  19. Haplotype Information and Linkage Disequilibrium Mapping for Single Nucleotide Polymorphisms

    Lu, Xin; Niu, Tianhua; Liu, Jun

    2003-01-01

    Single nucleotide polymorphisms in the human genome have become an increasingly popular topic in that their analyses promise to be a key step toward personalized medicine. We investigate two related questions, how much the haplotype information contributes to linkage disequilibrium (LD) mapping and whether an in silico haplotype construction preceding the LD analysis can help. For disease gene mapping, using both simulated and real data sets on cystic fibrosis and the Alzheimer disease, we re...

  20. Haplotype Information and Linkage Disequilibrium Mapping for Single Nucleotide Polymorphisms

    Lu, Xin; Niu, Tianhua; Liu, Jun S.

    2003-01-01

    Single nucleotide polymorphisms in the human genome have become an increasingly popular topic in that their analyses promise to be a key step toward personalized medicine. We investigate two related questions, how much the haplotype information contributes to linkage disequilibrium (LD) mapping and whether an in silico haplotype construction preceding the LD analysis can help. For disease gene mapping, using both simulated and real data sets on cystic fibrosis and the Alzheimer disease,...

  1. MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms

    Iatsyshyna A. P.; Pidpala O. V.; Lukash L. L.

    2013-01-01

    High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT) gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs) of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs o...

  2. Single nucleotide polymorphisms predict symptom severity of autism spectrum disorder

    Jiao, Yun; Chen, Rong; Ke, Xiaoyan; Cheng, Lu; Chu, Kangkang; Lu, Zuhong; Herskovits, Edward H

    2012-01-01

    Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs) can predict symptom severity of autism spectrum disorder (ASD). We divided 118 ASD children into a mild/moderate autism group (n = 65) and a severe a...

  3. Analysis of Single Nucleotide Polymorphism Panels for Bovine DNA Identification

    Blanchard, Kimberly A.

    2013-01-01

    Single nucleotide polymorphisms (SNPs) are single base-pair variations that exist between individuals. There are approximately a million or more SNPs located throughout the genome of each individual animal. Therefore, by taking advantage of these unique polymorphisms, SNPs can be used to resolve questions of unknown parentage in the livestock industry. Currently a panel of 88 SNPs, obtained from a panel of 121 SNPs originally created by USDA-MARC, is commercially available from Fluidigm®. The...

  4. Monovar: single-nucleotide variant detection in single cells.

    Zafar, Hamim; Wang, Yong; Nakhleh, Luay; Navin, Nicholas; Chen, Ken

    2016-06-01

    Current variant callers are not suitable for single-cell DNA sequencing, as they do not account for allelic dropout, false-positive errors and coverage nonuniformity. We developed Monovar (https://bitbucket.org/hamimzafar/monovar), a statistical method for detecting and genotyping single-nucleotide variants in single-cell data. Monovar exhibited superior performance over standard algorithms on benchmarks and in identifying driver mutations and delineating clonal substructure in three different human tumor data sets. PMID:27088313

  5. Single-nucleotide polymorphism identification and genotyping in Camelina sativa

    Singh, Ravinder; Bollina, Venkatesh; Higgins, Erin E.; Clarke, Wayne E.; Eynck, Christina; Sidebottom, Christine; Gugel, Richard; Snowdon, Rod; Parkin, Isobel A. P.

    2015-01-01

    Camelina sativa, a largely relict crop, has recently returned to interest due to its potential as an industrial oilseed. Molecular markers are key tools that will allow C. sativa to benefit from modern breeding approaches. Two complementary methodologies, capture of 3′ cDNA tags and genomic reduced-representation libraries, both of which exploited second generation sequencing platforms, were used to develop a low density (768) Illumina GoldenGate single nucleotide polymorphism (SNP) array. Th...

  6. Assessment of Genetic Diversity in Faba Bean Based on Single Nucleotide Polymorphism

    Sukhjiwan Kaur

    2014-01-01

    Full Text Available Detection of genetic diversity is important for characterisation of crop plant collections in order to detect the presence of valuable trait variation for use in breeding programs. A collection of faba bean (Vicia faba L. genotypes was evaluated for intra- and inter-population diversity using a set of 768 genome-wide distributed single nucleotide polymorphism (SNP markers, of which 657 obtained successful amplification and detected polymorphisms. Gene diversity and polymorphism information content (PIC values varied between 0.022–0.500 and 0.023–1.00, with averages of 0.363 and 0.287, respectively. The genetic structure of the germplasm collection was analysed and a neighbour-joining (NJ dendrogram was constructed. The faba bean accessions grouped into two major groups, with several additional smaller sub-groups, predominantly on the basis of geographical origin. These results were further supported by principal co-ordinate analysis (PCoA, deriving two major groupings which were differentiated on the basis of site of origin and pedigree relationships. In general, high levels of heterozygosity were observed, presumably due to the partially allogamous nature of the species. The results will facilitate targeted crossing strategies in future faba bean breeding programs in order to achieve genetic gain.

  7. Novel single nucleotide polymorphism markers for low dose aspirin-associated small bowel bleeding.

    Akiko Shiotani

    Full Text Available BACKGROUND: Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established. AIM: To investigate pharmacogenomic profile of low dose aspirin (LDA-induced small bowel bleeding. METHODS: Genome-wide analysis of single nucleotide polymorphisms (SNPs was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing. RESULTS: In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463 GG (p=0.003, CYP2D6 (rs28360521 GG (p=0.02, CYP24A1 (rs4809957 T allele (p=0.04, and GSTP1 (rs1695 G allele (p=0.04 were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521 GG (OR 4.11, 95% CI. 1.62 -10.4 was associated with small bowel bleeding. CONCLUSIONS: CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.

  8. Associations between single nucleotide polymorphisms in iron-related genes and iron status in multiethnic populations.

    Christine E McLaren

    Full Text Available The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs using DNA from white men aged ≥ 25 y and women ≥ 50 y in the Hemochromatosis and Iron Overload Screening (HEIRS Study with serum ferritin (SF ≤ 12 µg/L (cases and controls (SF >100 µg/L in men, SF >50 µg/L in women. We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7 × 10(-6 and replicated in African Americans (p = 0.0012.Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4 × 10(-5; six SNPs replicated in other ethnicities (p<0.01. SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0 × 10(-5. These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder.

  9. From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases

    Raghavan Chinnadurai

    2013-01-01

    Full Text Available The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS, linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs.

  10. Further development of multiplex single nucleotide polymorphism typing method, the DigiTag2 assay.

    Nishida, Nao; Tanabe, Tetsuya; Takasu, Miwa; Suyama, Akira; Tokunaga, Katsushi

    2007-05-01

    A number of single nucleotide polymorphisms (SNPs) are considered to be candidate susceptibility or resistance genetic factors for multifactorial disease. Genome-wide searches for disease susceptibility regions followed by high-resolution mapping of primary genes require cost-effective and highly reliable technology. To accomplish successful and low-cost typing for candidate SNPs, new technologies must be developed. We previously reported a multiplex SNP typing method, designated the DigiTag assay, that has the potential to analyze nearly any SNP with high accuracy and reproducibility. However, the DigiTag assay requires multiple washing steps in manipulation and uses genotyping probes modified with biotin for each target SNP. Here we describe the next version of the assay, DigiTag2, which works with simple protocols and uses unmodified genotyping probes. We investigated the feasibility of the DigiTag2 assay by genotyping 96 target SNPs spanning a 610-kb region of human chromosome 5. The DigiTag2 assay is suitable for genotyping an intermediate number of SNPs (tens to hundreds of sites) with a high conversion rate (>90%), high accuracy, and low cost. PMID:17359929

  11. A single-nucleotide polymorphism of human neuropeptide s gene originated from Europe shows decreased bioactivity.

    Cheng Deng

    Full Text Available Using accumulating SNP (Single-Nucleotide Polymorphism data, we performed a genome-wide search for polypeptide hormone ligands showing changes in the mature regions to elucidate genotype/phenotype diversity among various human populations. Neuropeptide S (NPS, a brain peptide hormone highly conserved in vertebrates, has diverse physiological effects on anxiety, fear, hyperactivity, food intake, and sleeping time through its cognate receptor-NPSR. Here, we report a SNP rs4751440 (L(6-NPS causing non-synonymous substitution on the 6(th position (V to L of the NPS mature peptide region. L(6-NPS has a higher allele frequency in Europeans than other populations and probably originated from European ancestors ~25,000 yrs ago based on haplotype analysis and Approximate Bayesian Computation. Functional analyses indicate that L(6-NPS exhibits a significant lower bioactivity than the wild type NPS, with ~20-fold higher EC50 values in the stimulation of NPSR. Additional evolutionary and mutagenesis studies further demonstrate the importance of the valine residue in the 6(th position for NPS functions. Given the known physiological roles of NPS receptor in inflammatory bowel diseases, asthma pathogenesis, macrophage immune responses, and brain functions, our study provides the basis to elucidate NPS evolution and signaling diversity among human populations.

  12. Genome-wide view of genetic diversity reveals paths of selection and cultivar differentiation in peach domestication.

    Akagi, Takashi; Hanada, Toshio; Yaegaki, Hideaki; Gradziel, Thomas M; Tao, Ryutaro

    2016-06-01

    Domestication and cultivar differentiation are requisite processes for establishing cultivated crops. These processes inherently involve substantial changes in population structure, including those from artificial selection of key genes. In this study, accessions of peach (Prunus persica) and its wild relatives were analysed genome-wide to identify changes in genetic structures and gene selections associated with their differentiation. Analysis of genome-wide informative single-nucleotide polymorphism loci revealed distinct changes in genetic structures and delineations among domesticated peach and its wild relatives and among peach landraces and modern fruit (F) and modern ornamental (O-A) cultivars. Indications of distinct changes in linkage disequilibrium extension/decay and of strong population bottlenecks or inbreeding were identified. Site frequency spectrum- and extended haplotype homozygosity-based evaluation of genome-wide genetic diversities supported selective sweeps distinguishing the domesticated peach from its wild relatives and each F/O-A cluster from the landrace clusters. The regions with strong selective sweeps harboured promising candidates for genes subjected to selection. Further sequence-based evaluation further defined the candidates and revealed their characteristics. All results suggest opportunities for identifying critical genes associated with each differentiation by analysing genome-wide genetic diversity in currently established populations. This approach obviates the special development of genetic populations, which is particularly difficult for long-lived tree crops. PMID:27085183

  13. Genome-wide view of genetic diversity reveals paths of selection and cultivar differentiation in peach domestication

    Akagi, Takashi; Hanada, Toshio; Yaegaki, Hideaki; Gradziel, Thomas M.; Tao, Ryutaro

    2016-01-01

    Domestication and cultivar differentiation are requisite processes for establishing cultivated crops. These processes inherently involve substantial changes in population structure, including those from artificial selection of key genes. In this study, accessions of peach (Prunus persica) and its wild relatives were analysed genome-wide to identify changes in genetic structures and gene selections associated with their differentiation. Analysis of genome-wide informative single-nucleotide polymorphism loci revealed distinct changes in genetic structures and delineations among domesticated peach and its wild relatives and among peach landraces and modern fruit (F) and modern ornamental (O-A) cultivars. Indications of distinct changes in linkage disequilibrium extension/decay and of strong population bottlenecks or inbreeding were identified. Site frequency spectrum- and extended haplotype homozygosity-based evaluation of genome-wide genetic diversities supported selective sweeps distinguishing the domesticated peach from its wild relatives and each F/O-A cluster from the landrace clusters. The regions with strong selective sweeps harboured promising candidates for genes subjected to selection. Further sequence-based evaluation further defined the candidates and revealed their characteristics. All results suggest opportunities for identifying critical genes associated with each differentiation by analysing genome-wide genetic diversity in currently established populations. This approach obviates the special development of genetic populations, which is particularly difficult for long-lived tree crops. PMID:27085183

  14. Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration.

    Scheinfeldt, Laura B; Gharani, Neda; Kasper, Rachel S; Schmidlen, Tara J; Gordon, Erynn S; Jarvis, Joseph P; Delaney, Susan; Kronenthal, Courtney J; Gerry, Norman P; Christman, Michael F

    2015-12-01

    Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome-wide association studies (GWAS). However, genome-wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self-reported sleep duration, demographic and lifestyle variables, and genome-wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration. We employed stepwise ordered logistic regression to select our model and retained the following predictive variables: age, gender, weight, physical activity, physical activity at work, smoking status, alcohol consumption, ethnicity, and ancestry (as measured by principal components analysis) in our association testing. Several of our strongest candidate genes were previously identified in GWAS related to sleep duration (TSHZ2, ABCC9, FBXO15) and narcolepsy (NFATC2, SALL4). In addition, we have identified novel candidate genes for involvement in sleep duration including SORCS1 and ELOVL2. Our results demonstrate that the self-reported data collected through the CPMC are robust, and our genome-wide association analysis has identified novel candidate genes involved in sleep duration. More generally, this study contributes to a better understanding of the complexity of human sleep. PMID:26333835

  15. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042

    Milne, Roger L; Benítez, Javier; Nevanlinna, Heli;

    2009-01-01

    -rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity......BACKGROUND: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. METHODS: 2q35......, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. RESULTS: We found strong...

  16. Single-Nucleotide Variations in Cardiac Arrhythmias: Prospects for Genomics and Proteomics Based Biomarker Discovery and Diagnostics

    Ayman Abunimer

    2014-03-01

    Full Text Available Cardiovascular diseases are a large contributor to causes of early death in developed countries. Some of these conditions, such as sudden cardiac death and atrial fibrillation, stem from arrhythmias—a spectrum of conditions with abnormal electrical activity in the heart. Genome-wide association studies can identify single nucleotide variations (SNVs that may predispose individuals to developing acquired forms of arrhythmias. Through manual curation of published genome-wide association studies, we have collected a comprehensive list of 75 SNVs associated with cardiac arrhythmias. Ten of the SNVs result in amino acid changes and can be used in proteomic-based detection methods. In an effort to identify additional non-synonymous mutations that affect the proteome, we analyzed the post-translational modification S-nitrosylation, which is known to affect cardiac arrhythmias. We identified loss of seven known S-nitrosylation sites due to non-synonymous single nucleotide variations (nsSNVs. For predicted nitrosylation sites we found 1429 proteins where the sites are modified due to nsSNV. Analysis of the predicted S-nitrosylation dataset for over- or under-representation (compared to the complete human proteome of pathways and functional elements shows significant statistical over-representation of the blood coagulation pathway. Gene Ontology (GO analysis displays statistically over-represented terms related to muscle contraction, receptor activity, motor activity, cystoskeleton components, and microtubule activity. Through the genomic and proteomic context of SNVs and S-nitrosylation sites presented in this study, researchers can look for variation that can predispose individuals to cardiac arrhythmias. Such attempts to elucidate mechanisms of arrhythmia thereby add yet another useful parameter in predicting susceptibility for cardiac diseases.

  17. Genome-wide association study of insect bite hypersensitivity in two horse populations in the Netherlands

    Schurink Anouk

    2012-10-01

    Full Text Available Abstract Background Insect bite hypersensitivity is a common allergic disease in horse populations worldwide. Insect bite hypersensitivity is affected by both environmental and genetic factors. However, little is known about genes contributing to the genetic variance associated with insect bite hypersensitivity. Therefore, the aim of our study was to identify and quantify genomic associations with insect bite hypersensitivity in Shetland pony mares and Icelandic horses in the Netherlands. Methods Data on 200 Shetland pony mares and 146 Icelandic horses were collected according to a matched case–control design. Cases and controls were matched on various factors (e.g. region, sire to minimize effects of population stratification. Breed-specific genome-wide association studies were performed using 70 k single nucleotide polymorphisms genotypes. Bayesian variable selection method Bayes-C with a threshold model implemented in GenSel software was applied. A 1 Mb non-overlapping window approach that accumulated contributions of adjacent single nucleotide polymorphisms was used to identify associated genomic regions. Results The percentage of variance explained by all single nucleotide polymorphisms was 13% in Shetland pony mares and 28% in Icelandic horses. The 20 non-overlapping windows explaining the largest percentages of genetic variance were found on nine chromosomes in Shetland pony mares and on 14 chromosomes in Icelandic horses. Overlap in identified associated genomic regions between breeds would suggest interesting candidate regions to follow-up on. Such regions common to both breeds (within 15 Mb were found on chromosomes 3, 7, 11, 20 and 23. Positional candidate genes within 2 Mb from the associated windows were identified on chromosome 20 in both breeds. Candidate genes are within the equine lymphocyte antigen class II region, which evokes an immune response by recognizing many foreign molecules. Conclusions The genome-wide association

  18. Genome Wide Methylome Alterations in Lung Cancer.

    Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; pLAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  19. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

    Brandl, E J; Tiwari, A K; Zai, C C; Nurmi, E L; Chowdhury, N I; Arenovich, T; Sanches, M; Goncalves, V F; Shen, J J; Lieberman, J A; Meltzer, H Y; Kennedy, J L; Müller, D J

    2016-08-01

    Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59. PMID:26323598

  20. Genome-wide scans using archived neonatal dried blood spot samples

    Wiuf Carsten

    2009-07-01

    Full Text Available Abstract Background Identification of disease susceptible genes requires access to DNA from numerous well-characterised subjects. Archived residual dried blood spot samples from national newborn screening programs may provide DNA from entire populations and medical registries the corresponding clinical information. The amount of DNA available in these samples is however rarely sufficient for reliable genome-wide scans, and whole-genome amplification may thus be necessary. This study assess the quality of DNA obtained from different amplification protocols by evaluating fidelity and robustness of the genotyping of 610,000 single nucleotide polymorphisms, using the Illumina Infinium HD Human610-Quad BeadChip. Whole-genome amplified DNA from 24 neonatal dried blood spot samples stored between 15 to 25 years was tested, and high-quality genomic DNA from 8 of the same individuals was used as reference. Results Using 3.2 mm disks from dried blood spot samples the optimal DNA-extraction and amplification protocol resulted in call-rates between 99.15% – 99.73% (mean 99.56%, N = 16, and conflicts with reference DNA in only three per 10,000 genotype calls. Conclusion Whole-genome amplified DNA from archived neonatal dried blood spot samples can be used for reliable genome-wide scans and is a cost-efficient alternative to collecting new samples.

  1. Genome-wide scans of genetic variants for psychophysiological endophenotypes: a methodological overview.

    Iacono, William G; Malone, Stephen M; Vaidyanathan, Uma; Vrieze, Scott I

    2014-12-01

    This article provides an introductory overview of the investigative strategy employed to evaluate the genetic basis of 17 endophenotypes examined as part of a 20-year data collection effort from the Minnesota Center for Twin and Family Research. Included are characterization of the study samples, descriptive statistics for key properties of the psychophysiological measures, and rationale behind the steps taken in the molecular genetic study design. The statistical approach included (a) biometric analysis of twin and family data, (b) heritability analysis using 527,829 single nucleotide polymorphisms (SNPs), (c) genome-wide association analysis of these SNPs and 17,601 autosomal genes, (d) follow-up analyses of candidate SNPs and genes hypothesized to have an association with each endophenotype, (e) rare variant analysis of nonsynonymous SNPs in the exome, and (f) whole genome sequencing association analysis using 27 million genetic variants. These methods were used in the accompanying empirical articles comprising this special issue, Genome-Wide Scans of Genetic Variants for Psychophysiological Endophenotypes. PMID:25387703

  2. Genome-wide association study identifies 74 loci associated with educational attainment.

    Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

    2016-05-26

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. PMID:27225129

  3. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMcahon, Katherine D.; Mamlstrom, Rex R.

    2014-05-12

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ecotype model? of diversification, but not previously observed in natural populations.

  4. Genome-wide Selective Sweeps in Natural Bacterial Populations Revealed by Time-series Metagenomics

    Chan, Leong-Keat; Bendall, Matthew L.; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Foster, Brian; Kang, Dongwan; Tringe, Susannah G.; Bertilsson, Stefan; Moran, Mary Ann; Shade, Ashley; Newton, Ryan J.; Stevens, Sarah; McMahon, Katherine D.; Malmstrom, Rex R.

    2014-06-18

    Multiple evolutionary models have been proposed to explain the formation of genetically and ecologically distinct bacterial groups. Time-series metagenomics enables direct observation of evolutionary processes in natural populations, and if applied over a sufficiently long time frame, this approach could capture events such as gene-specific or genome-wide selective sweeps. Direct observations of either process could help resolve how distinct groups form in natural microbial assemblages. Here, from a three-year metagenomic study of a freshwater lake, we explore changes in single nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in populations of Chlorobiaceae and Methylophilaceae. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied considerably among closely related, co-occurring Methylophilaceae populations. SNP allele frequencies, as well as the relative abundance of certain genes, changed dramatically over time in each population. Interestingly, SNP diversity was purged at nearly every genome position in one of the Chlorobiaceae populations over the course of three years, while at the same time multiple genes either swept through or were swept from this population. These patterns were consistent with a genome-wide selective sweep, a process predicted by the ‘ecotype model’ of diversification, but not previously observed in natural populations.

  5. Genome-wide analysis of copy number variation in type 1 diabetes.

    Britney L Grayson

    Full Text Available Type 1 diabetes (T1D tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs. We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.

  6. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-01-01

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition. PMID:27097669

  7. Genome Wide Sampling Sequencing for SNP Genotyping: Methods, Challenges and Future Development.

    Jiang, Zhihua; Wang, Hongyang; Michal, Jennifer J; Zhou, Xiang; Liu, Bang; Woods, Leah C Solberg; Fuchs, Rita A

    2016-01-01

    Genetic polymorphisms, particularly single nucleotide polymorphisms (SNPs), have been widely used to advance quantitative, functional and evolutionary genomics. Ideally, all genetic variants among individuals should be discovered when next generation sequencing (NGS) technologies and platforms are used for whole genome sequencing or resequencing. In order to improve the cost-effectiveness of the process, however, the research community has mainly focused on developing genome-wide sampling sequencing (GWSS) methods, a collection of reduced genome complexity sequencing, reduced genome representation sequencing and selective genome target sequencing. Here we review the major steps involved in library preparation, the types of adapters used for ligation and the primers designed for amplification of ligated products for sequencing. Unfortunately, currently available GWSS methods have their drawbacks, such as inconsistency in the number of reads per sample library, the number of sites/targets per individual, and the number of reads per site/target, all of which result in missing data. Suggestions are proposed here to improve library construction, genotype calling accuracy, genome-wide marker density and read mapping rate. In brief, optimized GWSS library preparation should generate a unique set of target sites with dense distribution along chromosomes and even coverage per site across all individuals. PMID:26722221

  8. Genome-wide linkage and association analysis identifies major gene loci for guttural pouch tympany in Arabian and German warmblood horses.

    Julia Metzger

    Full Text Available Equine guttural pouch tympany (GPT is a hereditary condition affecting foals in their first months of life. Complex segregation analyses in Arabian and German warmblood horses showed the involvement of a major gene as very likely. Genome-wide linkage and association analyses including a high density marker set of single nucleotide polymorphisms (SNPs were performed to map the genomic region harbouring the potential major gene for GPT. A total of 85 Arabian and 373 German warmblood horses were genotyped on the Illumina equine SNP50 beadchip. Non-parametric multipoint linkage analyses showed genome-wide significance on horse chromosomes (ECA 3 for German warmblood at 16-26 Mb and 34-55 Mb and for Arabian on ECA15 at 64-65 Mb. Genome-wide association analyses confirmed the linked regions for both breeds. In Arabian, genome-wide association was detected at 64 Mb within the region with the highest linkage peak on ECA15. For German warmblood, signals for genome-wide association were close to the peak region of linkage at 52 Mb on ECA3. The odds ratio for the SNP with the highest genome-wide association was 0.12 for the Arabian. In conclusion, the refinement of the regions with the Illumina equine SNP50 beadchip is an important step to unravel the responsible mutations for GPT.

  9. Usefulness of single nucleotide polymorphism data for estimating population parameters.

    Kuhner, M K; Beerli, P; Yamato, J; Felsenstein, J

    2000-01-01

    Single nucleotide polymorphism (SNP) data can be used for parameter estimation via maximum likelihood methods as long as the way in which the SNPs were determined is known, so that an appropriate likelihood formula can be constructed. We present such likelihoods for several sampling methods. As a test of these approaches, we consider use of SNPs to estimate the parameter Theta = 4N(e)micro (the scaled product of effective population size and per-site mutation rate), which is related to the br...

  10. A novel statistic for genome-wide interaction analysis.

    Xuesen Wu; Hua Dong (Eds); Li Luo; Yun Zhu; Gang Peng; Reveille, John D.; Momiao Xiong

    2010-01-01

    Although great progress in genome-wide association studies (GWAS) has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide inte...

  11. Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations.

    Bendall, Matthew L; Stevens, Sarah Lr; Chan, Leong-Keat; Malfatti, Stephanie; Schwientek, Patrick; Tremblay, Julien; Schackwitz, Wendy; Martin, Joel; Pati, Amrita; Bushnell, Brian; Froula, Jeff; Kang, Dongwan; Tringe, Susannah G; Bertilsson, Stefan; Moran, Mary A; Shade, Ashley; Newton, Ryan J; McMahon, Katherine D; Malmstrom, Rex R

    2016-07-01

    Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005-2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the 'ecotype model' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment. PMID:26744812

  12. Genome-wide association of anthropometric traits in African- and African-derived populations.

    Kang, Sun J; Chiang, Charleston W K; Palmer, Cameron D; Tayo, Bamidele O; Lettre, Guillaume; Butler, Johannah L; Hackett, Rachel; Adeyemo, Adebowale A; Guiducci, Candace; Berzins, Ilze; Nguyen, Thutrang T; Feng, Tao; Luke, Amy; Shriner, Daniel; Ardlie, Kristin; Rotimi, Charles; Wilks, Rainford; Forrester, Terrence; McKenzie, Colin A; Lyon, Helen N; Cooper, Richard S; Zhu, Xiaofeng; Hirschhorn, Joel N

    2010-07-01

    Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations. PMID:20400458

  13. Genome Wide Methylome Alterations in Lung Cancer.

    Nandita Mullapudi

    Full Text Available Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC, we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T-non-tumor (NT pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16. Further, when DM was coupled to differential transcriptome (DE in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

  14. Single nucleotide polymorphism analysis of European archaeological M. leprae DNA.

    Claire L Watson

    Full Text Available BACKGROUND: Leprosy was common in Europe eight to twelve centuries ago but molecular confirmation of this has been lacking. We have extracted M. leprae ancient DNA (aDNA from medieval bones and single nucleotide polymorphism (SNP typed the DNA, this provides insight into the pattern of leprosy transmission in Europe and may assist in the understanding of M. leprae evolution. METHODS AND FINDINGS: Skeletons have been exhumed from 3 European countries (the United Kingdom, Denmark and Croatia and are dated around the medieval period (476 to 1350 A.D.. we tested for the presence of 3 previously identified single nucleotide polymorphisms (SNPs in 10 aDNA extractions. M. leprae aDNA was extracted from 6 of the 10 bone samples. SNP analysis of these 6 extractions were compared to previously analysed European SNP data using the same PCR assays and were found to be the same. Testing for the presence of SNPs in M. leprae DNA extracted from ancient bone samples is a novel approach to analysing European M. leprae DNA and the findings concur with the previously published data that European M. leprae strains fall in to one group (SNP group 3. CONCLUSIONS: These findings support the suggestion that the M. leprae genome is extremely stable and show that archaeological M. leprae DNA can be analysed to gain detailed information about the genotypic make-up of European leprosy, which may assist in the understanding of leprosy transmission worldwide.

  15. A Multipurpose, High-Throughput Single-Nucleotide Polymorphism Chip for the Dengue and Yellow Fever Mosquito, Aedes aegypti.

    Evans, Benjamin R; Gloria-Soria, Andrea; Hou, Lin; McBride, Carolyn; Bonizzoni, Mariangela; Zhao, Hongyu; Powell, Jeffrey R

    2015-05-01

    The dengue and yellow fever mosquito, Aedes aegypti, contributes significantly to global disease burden. Genetic study of Aedes aegypti is essential to understanding its evolutionary history, competence as a disease vector, and the effects and efficacy of vector control methods. The prevalence of repeats and transposable elements in the Aedes aegypti genome complicates marker development and makes genome-wide genetic study challenging. To overcome these challenges, we developed a high-throughput genotyping chip, Axiom_aegypti1. This chip screens for 50,000 single-nucleotide polymorphisms present in Aedes aegypti populations from around the world. The array currently used genotypes 96 samples simultaneously. To ensure that these markers satisfy assumptions commonly made in many genetic analyses, we tested for Mendelian inheritance and linkage disequilibrium in laboratory crosses and a wild population, respectively. We have validated more than 25,000 of these markers to date, and expect this number to increase with more sampling. We also present evidence of the chip's efficacy in distinguishing populations throughout the world. The markers on this chip are ideal for applications ranging from population genetics to genome-wide association studies. This tool makes rapid, cost-effective, and comparable genotype data attainable to diverse sets of Aedes aegypti researchers, from those interested in potential range shifts due to climate change to those characterizing the genetic underpinnings of its competence to transmit disease. PMID:25721127

  16. Identification of copy number variations in three Chinese horse breeds using 70K single nucleotide polymorphism BeadChip array.

    Kader, Adiljan; Liu, Xuexue; Dong, Kunzhe; Song, Shen; Pan, Jianfei; Yang, Min; Chen, Xiaofei; He, Xiaohong; Jiang, Lin; Ma, Yuehui

    2016-10-01

    Copy number variation (CNV), an essential form of genetic variation, has been increasingly recognized as one promising genetic marker in the analysis of animal genomes. Here, we used the Equine 70K single nucleotide polymorphism genotyping array for the genome-wide detection of CNVs in 96 horses from three diverse Chinese breeds: Debao pony (DB), Mongolian horse (MG) and Yili horse (YL). A total of 287 CNVs were determined and merged into 122 CNV regions (CNVRs) ranging from 199 bp to 2344 kb in size and distributed in a heterogeneous manner on chromosomes. These CNVRs were integrated with seven existing reports to generate a composite genome-wide dataset of 1558 equine CNVRs, revealing 69 (56.6%) novel CNVRs. The majority (69.7%) of the 122 CNVRs overlapped with 438 genes, whereas 30.3% were located in intergenic regions. Most of these genes were associated with common CNVRs, which were shared by divergent horse breeds. As many as 60, 42 and 91 genes overlapping with the breed-specific ss were identified in DB, MG and YL respectively. Among these genes, FGF11, SPEM1, PPARG, CIDEB, HIVEP1 and GALR may have potential relevance to breed-specific traits. These findings provide valuable information for understanding the equine genome and facilitating association studies of economically important traits with equine CNVRs in the future. PMID:27440410

  17. Genome-wide prediction of agronomic traits in hybrid spring-type canola (Brassica napus) using single nucleotide polymorphic (SNP) markers

    Jan, Habib Ullah

    2016-01-01

    Canola/rapeseed (Brassica napus L., (AACC, 2n=38) is one of the world’s most important oilseed crops and is used as human food, i.e. cooking oil and as animal feed. In Europe, winter-type canola is also used as a sustainable source of bioenergy. Canola was naturally formed ~7500 years ago from spontaneous inter-specific hybridisations between cabbage (Brassica oleracea) and turnip rape (Brassica rapa). Recently, the reference genome of the B. napus ‘Darmor-bzh’ cultivar was sequenced and publ...

  18. Estimating Additive and Non-Additive Genetic Variances and Predicting Genetic Merits Using Genome-Wide Dense Single Nucleotide Polymorphism Markers

    Su, Guosheng; Christensen, Ole Fredslund; Ostersen, Tage; Henryon, Mark; Lund, Mogens Sandø

    2012-01-01

    of genomic predictions for daily gain in pigs. In the analysis of daily gain, four linear models were used: 1) a simple additive genetic model (MA), 2) a model including both additive and additive by additive epistatic genetic effects (MAE), 3) a model including both additive and dominance genetic...... effects (MAD), and 4) a full model including all three genetic components (MAED). Estimates of narrowsense heritability were 0.397, 0.373, 0.379 and 0.357 for models MA, MAE, MAD and MAED, respectively. Estimated dominance variance and additive by additive epistatic variance accounted for 5.6% and 9.5% of...... the total phenotypic variance, respectively. Based on model MAED, the estimate of broad-sense heritability was 0.506. Reliabilities of genomic predicted breeding values for the animals without performance records were 28.5%, 28.8%, 29.2% and 29.5% for models MA, MAE, MAD and MAED, respectively. In...

  19. Introgression of lineage c honey bees into black honey bee populations: a genome-wide estimation using single nucleotide polymorphisms (SNPS)

    Henriques, Dora; Chavez-Galarza, Julio; Kryger, Per; JOHNSTON, J. SPENCER; De La Rúa, Pilar; Rufino, José; Dall'Olio, Raffaele; Garnery, Lionel; Pinto, M. Alice

    2012-01-01

    The black honey bee, Apis mellifera mellifera L., is probably the honey bee subspecies more threatened by introgression from foreign subspecies, specially lineage C A. m. carnica and A. m. ligustica. In fact, in some areas of its distributional range, intensive beekeeping with foreign subspecies has driven A. m. mellifera populations to nearly replacement. While massive and repeated introductions may lead to loss of native genetic patrimony, a low level of gene flow can also be detrimental be...

  20. Pinched flow fractionation devices for detection of single nucleotide polymorphisms

    Larsen, A.V.; Poulsen, L.; Birgens, H.;

    2008-01-01

    We demonstrate a new and flexible micro fluidic based method for genotyping single nucleotide polymorphisms ( SNPs). The method relies on size separation of selectively hybridized polystyrene microspheres in a micro fluidic pinched flow fractionation (PFF) device. The micro fluidic PFF devices with......, synthesized using human DNA samples from individuals with point mutations in the HBB gene. Following a stringent wash, the beads were separated in a PFF device and the fluorescent signal from the beads was analyzed. Patients being wildtypes, heterozygotes or mutated respectively for the investigated mutation...... could reliably be diagnosed in the PFF device. This indicates that the PFF technique can be used for accurate and fast genotyping of SNPs Udgivelsesdato: 2008...

  1. Current research status, databases and application of single nucleotide polymorphism.

    Javed, R; Mukesh

    2010-07-01

    Single Nucleotide Polymorphisms (SNPs) are the most frequent form of DNA variation in the genome. SNPs are genetic markers which are bi-allelic in nature and grow at a very fast rate. Current genomic databases contain information on several million SNPs. More than 6 million SNPs have been identified and the information is publicly available through the efforts of the SNP Consortium and others data bases. The NCBI plays a major role in facillating the identification and cataloging of SNPs through creation and maintenance of the public SNP database (dbSNP) by the biomedical community worldwide and stimulate many areas of biological research including the identification of the genetic components of disease. In this review article, we are compiling the existing SNP databases, research status and their application. PMID:21717869

  2. Single nucleotide polymorphisms for assessing genetic diversity in castor bean (Ricinus communis

    Rabinowicz Pablo D

    2010-01-01

    Full Text Available Abstract Background Castor bean (Ricinus communis is an agricultural crop and garden ornamental that is widely cultivated and has been introduced worldwide. Understanding population structure and the distribution of castor bean cultivars has been challenging because of limited genetic variability. We analyzed the population genetics of R. communis in a worldwide collection of plants from germplasm and from naturalized populations in Florida, U.S. To assess genetic diversity we conducted survey sequencing of the genomes of seven diverse cultivars and compared the data to a reference genome assembly of a widespread cultivar (Hale. We determined the population genetic structure of 676 samples using single nucleotide polymorphisms (SNPs at 48 loci. Results Bayesian clustering indicated five main groups worldwide and a repeated pattern of mixed genotypes in most countries. High levels of population differentiation occurred between most populations but this structure was not geographically based. Most molecular variance occurred within populations (74% followed by 22% among populations, and 4% among continents. Samples from naturalized populations in Florida indicated significant population structuring consistent with local demes. There was significant population differentiation for 56 of 78 comparisons in Florida (pairwise population ϕPT values, p Conclusion Low levels of genetic diversity and mixing of genotypes have led to minimal geographic structuring of castor bean populations worldwide. Relatively few lineages occur and these are widely distributed. Our approach of determining population genetic structure using SNPs from genome-wide comparisons constitutes a framework for high-throughput analyses of genetic diversity in plants, particularly in species with limited genetic diversity.

  3. Whole Genome Association Study to Detect Single Nucleotide Polymorphisms for Behavior in Sapsaree Dog (Canis familiaris).

    Ha, J H; Alam, M; Lee, D H; Kim, J-J

    2015-07-01

    The purpose of this study was to characterize genetic architecture of behavior patterns in Sapsaree dogs. The breed population (n = 8,256) has been constructed since 1990 over 12 generations and managed at the Sapsaree Breeding Research Institute, Gyeongsan, Korea. Seven behavioral traits were investigated for 882 individuals. The traits were classified as a quantitative or a categorical group, and heritabilities (h(2)) and variance components were estimated under the Animal model using ASREML 2.0 software program. In general, the h(2) estimates of the traits ranged between 0.00 and 0.16. Strong genetic (r G ) and phenotypic (r P ) correlations were observed between nerve stability, affability and adaptability, i.e. 0.9 to 0.94 and 0.46 to 0.68, respectively. To detect significant single nucleotide polymorphism (SNP) for the behavioral traits, a total of 134 and 60 samples were genotyped using the Illumina 22K CanineSNP20 and 170K CanineHD bead chips, respectively. Two datasets comprising 60 (Sap60) and 183 (Sap183) samples were analyzed, respectively, of which the latter was based on the SNPs that were embedded on both the 22K and 170K chips. To perform genome-wide association analysis, each SNP was considered with the residuals of each phenotype that were adjusted for sex and year of birth as fixed effects. A least squares based single marker regression analysis was followed by a stepwise regression procedure for the significant SNPs (p<0.01), to determine a best set of SNPs for each trait. A total of 41 SNPs were detected with the Sap183 samples for the behavior traits. The significant SNPs need to be verified using other samples, so as to be utilized to improve behavior traits via marker-assisted selection in the Sapsaree population. PMID:26104397

  4. Identification and analysis of Single Nucleotide Polymorphisms (SNPs in the mosquito Anopheles funestus, malaria vector

    Hemingway Janet

    2007-01-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are the most common source of genetic variation in eukaryotic species and have become an important marker for genetic studies. The mosquito Anopheles funestus is one of the major malaria vectors in Africa and yet, prior to this study, no SNPs have been described for this species. Here we report a genome-wide set of SNP markers for use in genetic studies on this important human disease vector. Results DNA fragments from 50 genes were amplified and sequenced from 21 specimens of An. funestus. A third of specimens were field collected in Malawi, a third from a colony of Mozambican origin and a third form a colony of Angolan origin. A total of 494 SNPs including 303 within the coding regions of genes and 5 indels were identified. The physical positions of these SNPs in the genome are known. There were on average 7 SNPs per kilobase similar to that observed in An. gambiae and Drosophila melanogaster. Transitions outnumbered transversions, at a ratio of 2:1. The increased frequency of transition substitutions in coding regions is likely due to the structure of the genetic code and selective constraints. Synonymous sites within coding regions showed a higher polymorphism rate than non-coding introns or 3' and 5'flanking DNA with most of the substitutions in coding regions being observed at the 3rd codon position. A positive correlation in the level of polymorphism was observed between coding and non-coding regions within a gene. By genotyping a subset of 30 SNPs, we confirmed the validity of the SNPs identified during this study. Conclusion This set of SNP markers represents a useful tool for genetic studies in An. funestus, and will be useful in identifying candidate genes that affect diverse ranges of phenotypes that impact on vector control, such as resistance insecticide, mosquito behavior and vector competence.

  5. High-throughput single nucleotide polymorphism genotyping using nanofluidic Dynamic Arrays

    Crenshaw Andrew

    2009-01-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs have emerged as the genetic marker of choice for mapping disease loci and candidate gene association studies, because of their high density and relatively even distribution in the human genomes. There is a need for systems allowing medium multiplexing (ten to hundreds of SNPs with high throughput, which can efficiently and cost-effectively generate genotypes for a very large sample set (thousands of individuals. Methods that are flexible, fast, accurate and cost-effective are urgently needed. This is also important for those who work on high throughput genotyping in non-model systems where off-the-shelf assays are not available and a flexible platform is needed. Results We demonstrate the use of a nanofluidic Integrated Fluidic Circuit (IFC - based genotyping system for medium-throughput multiplexing known as the Dynamic Array, by genotyping 994 individual human DNA samples on 47 different SNP assays, using nanoliter volumes of reagents. Call rates of greater than 99.5% and call accuracies of greater than 99.8% were achieved from our study, which demonstrates that this is a formidable genotyping platform. The experimental set up is very simple, with a time-to-result for each sample of about 3 hours. Conclusion Our results demonstrate that the Dynamic Array is an excellent genotyping system for medium-throughput multiplexing (30-300 SNPs, which is simple to use and combines rapid throughput with excellent call rates, high concordance and low cost. The exceptional call rates and call accuracy obtained may be of particular interest to those working on validation and replication of genome- wide- association (GWA studies.

  6. NEDD4 single nucleotide polymorphism rs2271289 is associated with keloids in Chinese Han population.

    Zhao, Ying; Liu, Sheng-Li; Xie, Jian; Ding, Mao-Qian; Lu, Meng-Zhu; Zhang, Lan-Fang; Yao, Xiu-Hua; Hu, Bai; Lu, Wen-Sheng; Zheng, Xiao-Dong

    2016-01-01

    Keloids are abnormally raised fibroproliferative lesions that usually occur following cutaneous traumas. Recently, a large-scale genome-wide association study (GWAS) has identified multiple single nucleotide polymorphisms (SNPs) in three genetic loci that are associated with keloids in Japanese population. Subsequently, two reported loci 1q41 (rs873549 and rs1442440) and 15q21.3 (rs2271289) for keloids were confirmed in selected Chinese population. The association of these SNPs with clinical features of keloids, has not yet been studied. To explore the role of these SNPs in the pathogenesis of keloids, we performed a case-controlled study in another independent Chinese Han population to analyze the correlation between 4 SNPs (rs873549, rs2118610, rs1511412, rs2271289) and keloids phenotypes. 309 keloids patients and 1080 control subjects were included. The results showed that, in the dominant mode of inheritance, the minor allele T of SNP rs2271289 had significantly higher odd ratios (ORs) in the severe keloid group compared with both the controls and the mild keloid group. The ORs were maintained after Bonferroni's correction (OR: 4.09, 95% CI: 1.78-9.37, P-value 3.25E-04). The ratio of the severe: mild OR for rs2271289 (dominant model) is (4.73/1.84=2.57). Similar associations in SNP rs2271289 were seen for groups with no family history and multiplesite compared with the control groups. No associations between keloid number, family history or severity relative to the controls were observed for the other three SNPs. Our data support that rs2271289 is strongly associated with severe keloids and might contribute to the complexity of clinical features of keloids. PMID:27158346

  7. Common single nucleotide variants underlying drug addiction: more than a decade of research.

    Bühler, Kora-Mareen; Giné, Elena; Echeverry-Alzate, Victor; Calleja-Conde, Javier; de Fonseca, Fernando Rodriguez; López-Moreno, Jose Antonio

    2015-09-01

    Drug-related phenotypes are common complex and highly heritable traits. In the last few years, candidate gene (CGAS) and genome-wide association studies (GWAS) have identified a huge number of single nucleotide polymorphisms (SNPs) associated with drug use, abuse or dependence, mainly related to alcohol or nicotine. Nevertheless, few of these associations have been replicated in independent studies. The aim of this study was to provide a review of the SNPs that have been most significantly associated with alcohol-, nicotine-, cannabis- and cocaine-related phenotypes in humans between the years of 2000 and 2012. To this end, we selected CGAS, GWAS, family-based association and case-only studies published in peer-reviewed international scientific journals (using the PubMed/MEDLINE and Addiction GWAS Resource databases) in which a significant association was reported. A total of 371 studies fit the search criteria. We then filtered SNPs with at least one replication study and performed meta-analysis of the significance of the associations. SNPs in the alcohol metabolizing genes, in the cholinergic gene cluster CHRNA5-CHRNA3-CHRNB4, and in the DRD2 and ANNK1 genes, are, to date, the most replicated and significant gene variants associated with alcohol- and nicotine-related phenotypes. In the case of cannabis and cocaine, a far fewer number of studies and replications have been reported, indicating either a need for further investigation or that the genetics of cannabis/cocaine addiction are more elusive. This review brings a global state-of-the-art vision of the behavioral genetics of addiction and collaborates on formulation of new hypothesis to guide future work. PMID:25603899

  8. Genome-wide association analysis identifies loci for left-sided displacement of the abomasum in German Holstein cattle.

    Mömke, S; Sickinger, M; Lichtner, P; Doll, K; Rehage, J; Distl, O

    2013-06-01

    Left-sided displacement of the abomasum (LDA) is one of the most common disorders of the digestive system in many dairy breeds and particularly in Holstein dairy cows. We performed a genome-wide association study for 854 German Holstein cows, including 225 cases and 629 controls. All cows were genotyped using the Illumina Bovine SNP50 BeadChip (Illumina Inc., San Diego, CA). After quality control of genotypes, a total of 36,226 informative single nucleotide polymorphisms (SNP) were left for analysis. We used a mixed linear model approach for a genome-wide association study of LDA. In total, 36 SNP located on 17 bovine (Bos taurus) chromosomes (BTA) showed associations with LDA at nominal -log10P-values >3.0. Two of these SNP, located on BTA11 at 46.70 Mb and BTA20 at 16.67 Mb, showed genome-wide significant associations with LDA at -log10P-values >4.6. Pathway analyses indicated genes involved in calcium metabolism and insulin-dependent diabetes mellitus to be factors in the pathogenesis of LDA in German Holstein cows. PMID:23548285

  9. Genome-wide mapping of copy number variation in humans: comparative analysis of high resolution array platforms.

    Rajini R Haraksingh

    Full Text Available Accurate and efficient genome-wide detection of copy number variants (CNVs is essential for understanding human genomic variation, genome-wide CNV association type studies, cytogenetics research and diagnostics, and independent validation of CNVs identified from sequencing based technologies. Numerous, array-based platforms for CNV detection exist utilizing array Comparative Genome Hybridization (aCGH, Single Nucleotide Polymorphism (SNP genotyping or both. We have quantitatively assessed the abilities of twelve leading genome-wide CNV detection platforms to accurately detect Gold Standard sets of CNVs in the genome of HapMap CEU sample NA12878, and found significant differences in performance. The technologies analyzed were the NimbleGen 4.2 M, 2.1 M and 3×720 K Whole Genome and CNV focused arrays, the Agilent 1×1 M CGH and High Resolution and 2×400 K CNV and SNP+CGH arrays, the Illumina Human Omni1Quad array and the Affymetrix SNP 6.0 array. The Gold Standards used were a 1000 Genomes Project sequencing-based set of 3997 validated CNVs and an ultra high-resolution aCGH-based set of 756 validated CNVs. We found that sensitivity, total number, size range and breakpoint resolution of CNV calls were highest for CNV focused arrays. Our results are important for cost effective CNV detection and validation for both basic and clinical applications.

  10. Genome-wide Analysis of Ovate Family Proteins in Arabidopsis

    Huang Jian-ping; Li Hong-ling; Chang Ying

    2012-01-01

    Arabidopsis thaliana ovate family proteins (AtOFPs) is a newly found plant-specific protein family interacting with TALE (3-aa loop extension homeodomain proteins) homeodomain proteins in Arabidopsis. Here, based on bioinformatic analysis, we found that Arabidopsis genome actually encoded 17 OVATE domain-containing proteins. One of them, AtOFP19, has not been previously identified. Based on their amino acid sequence similarity, AtOFPs proteins can be divided into two groups. Most of the AtOFPs were located in nuclear, four of them were presented in chloroplast and the remaining two members appeared in cytoplasmic. A genome- wide microarray based gene expression analysis involving 47 stages of vegetative and reproductive development revealed that AtOFPs have diverse expression pattems. Investigation of proteins interaction showed that nine AtOFPs only interacted with TALE homeodomain proteins, which are fundamental regulators of plant meristem function and leaf development. Our work could provide important leads toward functional genomics studies of ovate family proteins, which may be involved in a previously unrecognized control mechanism in plant development

  11. Improved heritability estimation from genome-wide SNPs.

    Speed, D; Hemani, G.; Johnson, M. R.; Balding, D. J.

    2012-01-01

    Estimation of narrow-sense heritability, h(2), from genome-wide SNPs genotyped in unrelated individuals has recently attracted interest and offers several advantages over traditional pedigree-based methods. With the use of this approach, it has been estimated that over half the heritability of human height can be attributed to the ~300,000 SNPs on a genome-wide genotyping array. In comparison, only 5%-10% can be explained by SNPs reaching genome-wide significance. We investigated via simulati...

  12. Next-generation sequencing-based genome-wide mutation analysis of L-lysine-producing Corynebacterium glutamicum ATCC 21300 strain.

    Lee, Chang-Soo; Nam, Jae-Young; Son, Eun-Suk; Kwon, O-Chul; Han, Woorijarang; Cho, Jae-Yong; Park, Young-Jin

    2012-10-01

    In order to identify single nucleotide polymorphism and insertion/deletion mutations, we performed whole-genome re-sequencing of the enhanced L-lysine-producing Corynebacterium glutamicum ATCC 21300 strain. In total, 142 single nucleotide polymorphisms and 477 insertion/deletion mutations were identified in the ATCC 21300 strain when compared to 3,434 predicted genes of the wild-type C. glutamicum ATCC 13032 strain. Among them, 110 transitions and 29 transversions of single nucleotide polymorphisms were found from genes of the ATCC 21300 strain. In addition, 11 genes, involved in the L-lysine biosynthetic pathway and central carbohydrate metabolism, contained mutations including single nucleotide polymorphisms and insertions/deletions. Interestingly, RT-PCR analysis of these 11 genes indicated that they were normally expressed in the ATCC 21300 strain. This information of genome-wide gene-associated variations will be useful for genome breeding of C. glutamicum in order to develop an industrial amino acid-producing strain with minimal mutation. PMID:23124757

  13. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    ... 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A ... out to see if a technology called whole genome sequencing would help them find other genetic risk ...

  14. Genome-wide association study of clinical dimensions of schizophrenia

    Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H;

    2012-01-01

    Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.......Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia....

  15. Adjusted P values for genome-wide scans.

    Lystig, Theodore C.

    2003-01-01

    Genome-wide scans for quantitative trait loci (QTL) have traditionally been summarized with plots of logarithm of odds (LOD) scores. A valuable modification is to supplement such plots with an additional vertical axis displaying quantiles of adjusted P values and labeling local maxima of the LOD scores with location-specific adjusted P values. This provides a visible gradation of genome-wide significance for the LOD score curve, instead of the stark dichotomy that a single threshold yields. A...

  16. Phenome-wide analysis of genome-wide polygenic scores

    Krapohl, E; Euesden, J.; Zabaneh, D.; Pingault, J-B; Rimfeld, K; von Stumm, Sophie; Dale, P.S.; Breen, G.; O'Reilly, P. F.; Plomin, R

    2015-01-01

    Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia,...

  17. Generation of meiomaps of genome-wide recombination and chromosome segregation in human oocytes.

    Ottolini, Christian S; Capalbo, Antonio; Newnham, Louise; Cimadomo, Danilo; Natesan, Senthilkumar A; Hoffmann, Eva R; Ubaldi, Filippo M; Rienzi, Laura; Handyside, Alan H

    2016-07-01

    We have developed a protocol for the generation of genome-wide maps (meiomaps) of recombination and chromosome segregation for the three products of human female meiosis: the first and second polar bodies (PB1 and PB2) and the corresponding oocyte. PB1 is biopsied and the oocyte is artificially activated by exposure to calcium ionophore, after which PB2 is biopsied and collected with the corresponding oocyte. The whole genomes of the polar bodies and oocytes are amplified by multiple displacement amplification and, together with maternal genomic DNA, genotyped for ∼300,000 single-nucleotide polymorphisms (SNPs) genome-wide by microarray. Informative maternal heterozygous SNPs are phased using a haploid PB2 or oocyte as a reference. A simple algorithm is then used to identify the maternal haplotypes for each chromosome, in all of the products of meiosis for each oocyte. This allows mapping of crossovers and analysis of chromosome segregation patterns. The protocol takes a minimum of 3-5 d and requires a clinical embryologist with micromanipulation experience and a molecular biologist with basic bioinformatic skills. It has several advantages over previous methods; importantly, the use of artificial oocyte activation avoids the creation of embryos for research purposes. In addition, compared with next-generation sequencing, targeted SNP genotyping is cost-effective and it simplifies the bioinformatic analysis, as only one haploid reference sample is required to establish phase for maternal haplotyping. Finally, meiomapping is more informative than copy-number analysis alone for analysis of chromosome segregation patterns. Using this protocol, we have provided new insights that may lead to improvements in assisted reproduction for the treatment of infertility. PMID:27310263

  18. Genome-wide association study of retinopathy in individuals without diabetes.

    Richard A Jensen

    Full Text Available BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9 on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error, p = 6.6×10(-9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%, the quality of the imputation was moderate (r(2 ∼0.7, and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

  19. A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression

    Binder, Elisabeth B.; Bettecken, Thomas; Uhr, Manfred; Ripke, Stephan; Kohli, Martin A.; Hennings, Johannes M.; Horstmann, Sonja; Kloiber, Stefan; Menke, Andreas; Bondy, Brigitta; Rupprecht, Rainer; Domschke, Katharina; Baune, Bernhard T.; Arolt, Volker; Rush, A. John; Holsboer, Florian; Müller-Myhsok, Bertram

    2015-01-01

    Context Efficacy of antidepressant treatment in depression is unsatisfactory as one in three patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. Objective To identify genetic and clinical determinants of antidepressant treatment outcome in depression. Design Genome-wide pharmacogenetic association study with two independent replication samples. Setting We performed a genome-wide association (GWA) study in patients from the Munich-Antidepressant-Response-Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single nucleotide polymorphisms (SNPs) highly related to outcome in both GWA studies was genotyped in a sample of the Sequenced-Treatment-Alternatives-to-Relieve-Depression (STAR*D) study. Participants 339 inpatients suffering from a depressive episode (MARS sample), further 361 depressed inpatients (German replication sample), and 832 outpatients with major depression (STAR*D sample). Main Outcome Measures We generated a multi-locus genetic variable describing the individual number of alleles of the selected SNPs associated with beneficial treatment outcome in the MARS sample (“response” alleles) to evaluate additive genetic effects on antidepressant treatment outcome. Results Multi-locus analysis revealed a significant contribution of a binary variable categorizing patients as carriers of a high vs. low number of response alleles in predicting antidepressant treatment outcome in both samples, MARS and STAR*D. In addition, we observed that patients with a comorbid anxiety disorder in combination with a low number of response alleles showed the least favorable outcome. Conclusion Our results demonstrate the importance of multiple genetic factors in combination with clinical features to predict antidepressant treatment outcome underscoring the multifactorial nature of this trait. PMID

  20. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

    Mattheisen, M; Samuels, J F; Wang, Y; Greenberg, B D; Fyer, A J; McCracken, J T; Geller, D A; Murphy, D L; Knowles, J A; Grados, M A; Riddle, M A; Rasmussen, S A; McLaughlin, N C; Nurmi, E L; Askland, K D; Qin, H-D; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Liang, K-Y; Goes, F S; Maher, B; Pulver, A E; Shugart, Y Y; Valle, D; Lange, C; Nestadt, G

    2015-03-01

    Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples. PMID:24821223

  1. Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases.

    Murk, William; DeWan, Andrew T

    2016-01-01

    The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10(-12)). Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized. PMID:27185397

  2. Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases

    William Murk

    2016-07-01

    Full Text Available The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs with minor allele frequency (MAF ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10−12. Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized.

  3. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

    J Brent Richards

    2009-12-01

    Full Text Available The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D and coronary heart disease (CHD. We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531 and sought validation of the lead single nucleotide polymorphisms (SNPs in 5 additional cohorts (n = 6,202. Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8. We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19 for lead SNP, rs266717, n = 14,733. A novel variant in the ARL15 (ADP-ribosylation factor-like 15 gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8, n = 14,733. This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6, n = 22,421 more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3, n = 10,128, and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

  4. A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

    Rosella Mechelli

    Full Text Available Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.

  5. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

    Davies, G; Harris, S E; Reynolds, C A; Payton, A; Knight, H M; Liewald, D C; Lopez, L M; Luciano, M; Gow, A J; Corley, J; Henderson, R; Murray, C; Pattie, A; Fox, H C; Redmond, P; Lutz, M W; Chiba-Falek, O; Linnertz, C; Saith, S; Haggarty, P; McNeill, G; Ke, X; Ollier, W; Horan, M; Roses, A D; Ponting, C P; Porteous, D J; Tenesa, A; Pickles, A; Starr, J M; Whalley, L J; Pedersen, N L; Pendleton, N; Visscher, P M; Deary, I J

    2014-01-01

    Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear. PMID:23207651

  6. Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.

    Liu, Xiaoxi; Shimada, Takafumi; Otowa, Takeshi; Wu, Yu-Yu; Kawamura, Yoshiya; Tochigi, Mamoru; Iwata, Yasuhide; Umekage, Tadashi; Toyota, Tomoko; Maekawa, Motoko; Iwayama, Yoshimi; Suzuki, Katsuaki; Kakiuchi, Chihiro; Kuwabara, Hitoshi; Kano, Yukiko; Nishida, Hisami; Sugiyama, Toshiro; Kato, Nobumasa; Chen, Chia-Hsiang; Mori, Norio; Yamada, Kazuo; Yoshikawa, Takeo; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa; Gau, Susan Shur-Fen

    2016-03-01

    Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two-stage genome-wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome-Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254), were genotyped by TaqMan platform. Case-control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta-analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P = 6.04 × 10(-7) ), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD. Autism Res 2016, 9: 340-349. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID:26314684

  7. Genome-wide association study of coronary and aortic calcification in lung cancer screening CT

    de Vos, Bob D.; van Setten, Jessica; de Jong, Pim A.; Mali, Willem P.; Oudkerk, Matthijs; Viergever, Max A.; Išgum, Ivana

    2016-03-01

    Arterial calcification has been related to cardiovascular disease (CVD) and osteoporosis. However, little is known about the role of genetics and exact pathways leading to arterial calcification and its relation to bone density changes indicating osteoporosis. In this study, we conducted a genome-wide association study of arterial calcification burden, followed by a look-up of known single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and myocardial infarction (MI), and bone mineral density (BMD) to test for a shared genetic basis between the traits. The study included a subcohort of the Dutch-Belgian lung cancer screening trial comprised of 2,561 participants. Participants underwent baseline CT screening in one of two hospitals participating in the trial. Low-dose chest CT images were acquired without contrast enhancement and without ECG-synchronization. In these images coronary and aortic calcifications were identified automatically. Subsequently, the detected calcifications were quantified using coronary artery calcium Agatston and volume scores. Genotype data was available for these participants. A genome-wide association study was conducted on 10,220,814 SNPs using a linear regression model. To reduce multiple testing burden, known CAD/MI and BMD SNPs were specifically tested (45 SNPs from the CARDIoGRAMplusC4D consortium and 60 SNPS from the GEFOS consortium). No novel significant SNPs were found. Significant enrichment for CAD/MI SNPs was observed in testing Agatston and coronary artery calcium volume scores. Moreover, a significant enrichment of BMD SNPs was shown in aortic calcium volume scores. This may indicate genetic relation of BMD SNPs and arterial calcification burden.

  8. GWAMA: software for genome-wide association meta-analysis

    Mägi Reedik

    2010-05-01

    Full Text Available Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages incorporate routines for meta-analysis, they are ill equipped to meet the challenges of the scale and complexity of data generated in genome-wide association studies. Results We have developed flexible, open-source software for the meta-analysis of genome-wide association studies. The software incorporates a variety of error trapping facilities, and provides a range of meta-analysis summary statistics. The software is distributed with scripts that allow simple formatting of files containing the results of each association study and generate graphical summaries of genome-wide meta-analysis results. Conclusions The GWAMA (Genome-Wide Association Meta-Analysis software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits. Software with source files, documentation and example data files are freely available online at http://www.well.ox.ac.uk/GWAMA.

  9. Single Nucleotide Polymorphism Clustering in Systemic Autoimmune Diseases

    Charlon, Thomas; Bossini-Castillo, Lara; Carmona, F. David; Di Cara, Alessandro; Wojcik, Jérôme; Voloshynovskiy, Sviatoslav

    2016-01-01

    Systemic Autoimmune Diseases, a group of chronic inflammatory conditions, have variable symptoms and difficult diagnosis. In order to reclassify them based on genetic markers rather than clinical criteria, we performed clustering of Single Nucleotide Polymorphisms. However naive approaches tend to group patients primarily by their geographic origin. To reduce this “ancestry signal”, we developed SNPClust, a method to select large sources of ancestry-independent genetic variations from all variations detected by Principal Component Analysis. Applied to a Systemic Lupus Erythematosus case control dataset, SNPClust successfully reduced the ancestry signal. Results were compared with association studies between the cases and controls without or with reference population stratification correction methods. SNPClust amplified the disease discriminating signal and the ratio of significant associations outside the HLA locus was greater compared to population stratification correction methods. SNPClust will enable the use of ancestry-independent genetic information in the reclassification of Systemic Autoimmune Diseases. SNPClust is available as an R package and demonstrated on the public Human Genome Diversity Project dataset at https://github.com/ThomasChln/snpclust. PMID:27490238

  10. Single Nucleotide Polymorphism Clustering in Systemic Autoimmune Diseases.

    Charlon, Thomas; Martínez-Bueno, Manuel; Bossini-Castillo, Lara; Carmona, F David; Di Cara, Alessandro; Wojcik, Jérôme; Voloshynovskiy, Sviatoslav; Martín, Javier; Alarcón-Riquelme, Marta E

    2016-01-01

    Systemic Autoimmune Diseases, a group of chronic inflammatory conditions, have variable symptoms and difficult diagnosis. In order to reclassify them based on genetic markers rather than clinical criteria, we performed clustering of Single Nucleotide Polymorphisms. However naive approaches tend to group patients primarily by their geographic origin. To reduce this "ancestry signal", we developed SNPClust, a method to select large sources of ancestry-independent genetic variations from all variations detected by Principal Component Analysis. Applied to a Systemic Lupus Erythematosus case control dataset, SNPClust successfully reduced the ancestry signal. Results were compared with association studies between the cases and controls without or with reference population stratification correction methods. SNPClust amplified the disease discriminating signal and the ratio of significant associations outside the HLA locus was greater compared to population stratification correction methods. SNPClust will enable the use of ancestry-independent genetic information in the reclassification of Systemic Autoimmune Diseases. SNPClust is available as an R package and demonstrated on the public Human Genome Diversity Project dataset at https://github.com/ThomasChln/snpclust. PMID:27490238

  11. Single Nucleotide Polymorphism Analysis of Protamine Genes in Infertile Men

    Ahamad Salamian

    2008-01-01

    Full Text Available Background: Single nucleotide polymorphism (SNPs are considered as one of the underlyingcauses of male infertility. Proper sperm chromatin packaging which involves replacement ofhistones with protamines has profound effect on male fertility. Over 20 SNPs have been reportedfor the protamine 1 and 2.Materials and Methods: The aim of this study was to evaluate the frequency of two previouslyreported SNPs using polymerase chain reaction (PCR-restriction fragment length polymorphism(RFLP approach in 35, 96 and 177 normal, oligozoospermic and azoospermic individuals. TheseSNPs are: 1. A base pair substitution (G at position 197 instead of T in protamine type 1 Openreading frame (ORF including untranslated region, which causes an Arg residue change to Serresidue in a highly conserved region. 2. cytidine nucleotide change to thymidine in position of 248of protamine type 2 ORF which caused a nonsense point mutation.Results: The two mentioned SNPs were not present in the studied population, thus concluding thatthese SNPs can not serves as molecular markers for male infertility diagnosis.Conclusion: The results of our study reveal that in a selected Iranian population, the SNP G197Tand C248T are completely absent and are not associated with male infertility and therefore theseSNPs may not represent a molecular marker for genetic diagnosis of male infertility.

  12. Single nucleotide polymorphisms of Kit gene in Chinese indigenous horses.

    Han, Haoyuan; Mao, Chunchun; Chen, Ningbo; Lan, Xianyong; Chen, Hong; Lei, Chuzhao; Dang, Ruihua

    2016-02-01

    Kit gene is a genetic determinant of horse white coat color which has been a highly valued trait in horses for at least 2,000 years. Single nucleotide polymorphisms (SNPs) in Kit are of importance due to their strong associations with melanoblast survival during embryonic development. In this study, a mutation analysis of all 21 Kit exons in 14 Chinese domestic horse breeds revealed six SNPs (g.91214T>G, g.143245T>G, g.164297C>T, g.170189C>T, g.171356C>G, and g.171471G>A), which located in 5'-UTR region, intron 6, exon 15, exon 20, intron 20, and exon 21 of the equine Kit gene, respectively. Subsequently, these six SNPs loci were genotyped in 632 Chinese horses by PCR-RFLP or direct sequencing. The six SNPs together defined 18 haplotypes, demonstrating abundant haplotype diversities in Chinese horses. All the mutant alleles and haplotypes were shared among different breeds. But fewer mutations were detected in horses from China than that from abroad, indicating that Chinese horses belong to a more ancient genetic pool. This study will provide fundamental genetic information for evaluating the genetic diversity of Kit gene in Chinese indigenous horse breeds. PMID:27348891

  13. MGMT expression: insights into its regulation. 2. Single nucleotide polymorphisms

    Iatsyshyna A. P.

    2013-09-01

    Full Text Available High intra- and interindividual variations in the expression levels of the human O6-methylguanine-DNA methyltransferase (MGMT gene have been observed. This DNA repair enzyme can be a cause of resistance of cancer cells to alkylating chemotherapy. It has been studied the association of single nucleotide polymorphisms (SNPs of MGMT with the risk for different types of cancer, progression-free survival in patients with cancer treated with alkylating chemotherapy, as well as an effect of SNPs on the MGMT gene expression and activity of the enzyme. SNPs have been suggested to be the factors which influence the levels of interindividual variability of the MGMT expression. Therefore, the aim of this paper was to review the experimental data on SNPs of the human MGMT gene, which are associated with cancer, as well as on location of MGMT-SNPs in regulatory and protein-coding regions of the gene in relation to its regulation. Lots of MGMT SNPs, which could affect the gene expression and result in interindividual MGMT variability or the enzyme resistance to pseudosubstrate inhibitors, have been re- vealed within the promoter and enhancer regions, the 5'- and 3'-UTRs and introns of the MGMT gene, as well as within the protein-coding region. Many of them may have regulatory effect.

  14. Genome-wide association study identified PLCE1- rs2797992 and EGFR- rs6950826 were associated with TP53 expression in the HBV-related hepatocellular carcinoma of Chinese patients in Guangxi

    Liao, Xiwen; Han, Chuangye; Qin, Wei; Liu, Xiaoguang; Yu, Long; Lu, Sicong; Chen, Zhiwei; Zhu, Guangzhi; Su, Hao; Mo, Zengnan; Qin, Xue; Peng, Tao

    2016-01-01

    Objective: The genome-wide association approach was employed to explore the association between single nucleotide polymorphisms (SNPs) and TP53 expression in the HBV-related hepatocellular carcinoma (HCC) of Chinese patients in Guangxi. Methods: 403 HBV-related HCC patients were recruited into this study and classified according to the TP53 expression in the cancer by immunohistochemistry. DNA was extracted from the cancer and genotyped with the Human ExomeBeadChip 12v1-1 system; quality cont...

  15. The Association of Type 2 Diabetes Loci Identified in Genome-Wide Association Studies with Metabolic Syndrome and Its Components in a Chinese Population with Type 2 Diabetes

    Kong, Xiaomu; Zhang, Xuelian; Xing, Xiaoyan; Zhang, Bo; Hong, Jing; Yang, Wenying

    2015-01-01

    Metabolic syndrome (MetS) is prevalent in type 2 diabetes (T2D) patients. The comorbidity of MetS and T2D increases the risk of cardiovascular complications. The aim of the present study was to determine the T2D-related genetic variants that contribute to MetS-related components in T2D patients of Chinese ancestry. We successfully genotyped 25 genome wide association study validated T2D-related single nucleotide polymorphisms (SNPs) among 5,169 T2D individuals and 4,560 normal glycemic contro...

  16. Genome-wide scans of genetic variants for psychophysiological endophenotypes: introduction to this special issue of Psychophysiology.

    Iacono, William G

    2014-12-01

    This special issue addresses the heritability and molecular genetic basis of 17 putative endophenotypes involving resting EEG power, P300 event-related potential amplitude, electrodermal orienting and habituation, antisaccade eye tracking, and affective modulation of the startle eye blink. These measures were collected from approximately 4,900 twins and parents who provided DNA samples through their participation in the Minnesota Twin Family Study. Included are papers that detail the methodology followed, genome-wide association analyses of single nucleotide polymorphisms and genes, analysis of rare variants in the human exome, and a whole genome sequencing study. Also included are 11 articles by leading experts in psychophysiology and genetics that provide perspective and commentary. A final integrative report summarizes findings and addresses issues raised. This introduction provides an overview of the aims and rationale behind these studies. PMID:25387700

  17. [Future direction of pharmacogenomics: identification of genes associated with risk of adverse drug reactions using genome-wide association study].

    Mushiroda, Taisei

    2014-01-01

    Drug-induced skin rash characterized by an acute inflammatory reaction of skin and mucous membranes is dose-independent, unpredictable, and sometimes life-threatening. In recent years, the U.S. Food and Drug Administration (FDA) has recommended genotyping of polymorphisms in the human leukocyte antigen (HLA) prior to drug administration for the avoidance of severe skin rash induced by drugs, such as abacavir and carbamazepine. A genome-wide association study (GWAS) is useful for the identification of genomic biomarkers that can predict the efficacy or risk of toxicity of various drugs. We identified novel susceptibility loci associated with the risk of a skin rash induced by nevirapine and carbamazepine in Thai and Japanese populations, respectively, through case-control GWAS with high-throughput single-nucleotide polymorphism (SNP) genotyping technology. In order to apply the genomic biomarkers to clinical therapeutics, prospective clinical trials will be necessary for the evaluation of an intervention based on genetic tests. PMID:24724431

  18. Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness

    Bigdeli, Tim B; Ripke, Stephan; Bacanu, Silviu-Alin;

    2015-01-01

    of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N...... history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R(2 ) = 0.0021; P = 0.00331; P-value threshold ... = 978), cases reporting no such family history (N = 4,503), and unscreened controls (N = 8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history...

  19. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

    Hamshere, M L; Walters, J T R; Smith, R;

    2013-01-01

    -locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we......The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi...... obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with...

  20. Genome-wide association and pathway analysis of feed efficiency in pigs reveal candidate genes and pathways for residual feed intake

    Do, Duy Ngoc; Strathe, Anders Bjerring; Ostersen, Tage;

    2014-01-01

    Residual feed intake (RFI) is a complex trait that is economically important for livestock production; however, the genetic and biological mechanisms regulating RFI are largely unknown in pigs. Therefore, the study aimed to identify single nucleotide polymorphisms (SNPs), candidate genes and...... biological pathways involved in regulating RFI using Genome-wide association (GWA) and pathway analyses. A total of 596 Yorkshire boars with phenotypes for two different measures of RFI (RFI1 and 2) and 60k genotypic data was used. Genome-wide association analysis was performed using a univariate mixed model...... and 12 and 7 SNPs were found to be significantly associated with RFI1 and RFI2, respectively. Several genes such as XIRP2, TTC29, SOGA1, MAS1, GRK5, PROX1, GPR155 and ZFYVE26 were identified as putative candidates for RFI based on their genomic location in the vicinity of these SNPs. Genes located...

  1. Sequencing genes in silico using single nucleotide polymorphisms

    Zhang Xinyi

    2012-01-01

    Full Text Available Abstract Background The advent of high throughput sequencing technology has enabled the 1000 Genomes Project Pilot 3 to generate complete sequence data for more than 906 genes and 8,140 exons representing 697 subjects. The 1000 Genomes database provides a critical opportunity for further interpreting disease associations with single nucleotide polymorphisms (SNPs discovered from genetic association studies. Currently, direct sequencing of candidate genes or regions on a large number of subjects remains both cost- and time-prohibitive. Results To accelerate the translation from discovery to functional studies, we propose an in silico gene sequencing method (ISS, which predicts phased sequences of intragenic regions, using SNPs. The key underlying idea of our method is to infer diploid sequences (a pair of phased sequences/alleles at every functional locus utilizing the deep sequencing data from the 1000 Genomes Project and SNP data from the HapMap Project, and to build prediction models using flanking SNPs. Using this method, we have developed a database of prediction models for 611 known genes. Sequence prediction accuracy for these genes is 96.26% on average (ranges 79%-100%. This database of prediction models can be enhanced and scaled up to include new genes as the 1000 Genomes Project sequences additional genes on additional individuals. Applying our predictive model for the KCNJ11 gene to the Wellcome Trust Case Control Consortium (WTCCC Type 2 diabetes cohort, we demonstrate how the prediction of phased sequences inferred from GWAS SNP genotype data can be used to facilitate interpretation and identify a probable functional mechanism such as protein changes. Conclusions Prior to the general availability of routine sequencing of all subjects, the ISS method proposed here provides a time- and cost-effective approach to broadening the characterization of disease associated SNPs and regions, and facilitating the prioritization of candidate

  2. Genome-Wide Association Study Identifies Candidate Loci Associated with Platelet Count in Koreans

    Oh, Ji Hee; Kim, Yun Kyoung; Moon, Sanghoon; Kim, Young Jin

    2014-01-01

    Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction. Here, we performed a genome-wide association study with 352,228 single-nucleotide polymorphisms typed in 8,842 subjects of the Korea Association Resource (KARE) project and replicated the results in 7,861 subjects from an independent population. We identified genetic associations between platelet count and common variants nearby chromosome 4p16.1 (p = 1.46 × 10-10, in the KIAA0232 gene), 6p21 (p = 1.36 × 10-7, in the BAK1 gene), and 12q24.12 (p = 1.11 × 10-15, in the SH2B3 gene). Our results illustrate the value of large-scale discovery and a focus for several novel research avenues. PMID:25705162

  3. Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Donohoe, G; Walters, J; Hargreaves, A; Rose, E J; Morris, D W; Fahey, C; Bellini, S; Cummins, E; Giegling, I; Hartmann, A M; Möller, H-J; Muglia, P; Owen, M J; Gill, M; O'Donovan, M C; Tropea, D; Rujescu, D; Corvin, A

    2013-03-01

    The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk. PMID:23320435

  4. A genome-wide association study of the metabolic syndrome in Indian Asian men.

    Delilah Zabaneh

    Full Text Available We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits: HDL-cholesterol, plasma glucose and Type 2 diabetes, abdominal obesity measured by waist to hip ratio, and diastolic blood pressure. Association was tested with these four traits and a composite metabolic syndrome phenotype. Four SNPs reaching significance level p0.8 were found in genes CETP and LPL, associated with HDL-cholesterol. These associations have already been reported in Indian Asians and in Europeans. Five additional loci harboured SNPs significant at p0.5 for HDL-cholesterol, type 2 diabetes or diastolic blood pressure. Our results suggest that the primary genetic determinants of metabolic syndrome are the same in Indian Asians as in other populations, despite the higher prevalence. Further, we found little evidence of a common genetic basis for metabolic syndrome traits in our sample of Indian Asian men.

  5. Agronomic and Seed Quality Traits Dissected by Genome-Wide Association Mapping in Brassica napus.

    Körber, Niklas; Bus, Anja; Li, Jinquan; Parkin, Isobel A P; Wittkop, Benjamin; Snowdon, Rod J; Stich, Benjamin

    2016-01-01

    In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i) genome regions associated with the examined agronomic and seed quality traits, (ii) the interrelationship of population structure and the detected associations, and (iii) candidate genes for the revealed associations. The diversity set used in this study consisted of 405 B. napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP) array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations. PMID:27066036

  6. Agronomic and seed quality traits dissected by genome-wide association mapping in Brassica napus

    Niklas eKörber

    2016-03-01

    Full Text Available In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. % as well as require high experimental effort due to their quantitative inheritance and the importance of genotype*environment interaction. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i genome regions associated with the examined agronomic and seed quality traits, (ii the interrelationship of population structure and the detected associations, and (iii candidate genes for the revealed associations. The diversity set used in this study consisted of 405 Brassica napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P-value 100 and a sequence identity of > 70 % to A. thaliana or B. rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations.

  7. [Genome-Wide Association Studies for life-style related diseases].

    Maeda, Shiro

    2016-03-01

    After the completion of human genome project, development of single nucleotide polymorphism (SNP) typing technology and collation of information regarding linkage disequilibrium in the human genome have facilitated genome-wide association studies (GWAS) for investigating genes associated with disease susceptibility across the entire human genome. In case of type 2 diabetes, approximately 100 genetic loci have been identified and confirmed as susceptibility to the disease through GWAS in different ethnic groups, including Japanese, European, East Asian and South Asian populations. However, integration of these information accounts for less than 20% of the disease heritability, and thus most of the heritability of type 2 diabetes remain to be identified. Since the rationale of GWAS is based on the hypothesis that common variants contribute to the susceptibility to common diseases, common disease-common variant hypothesis, GWAS have selectively identified common susceptibility variants (allele frequency>=0.05) with lower effect size (odds ratiogenome sequencing to identify rare variants with greater effect size or integration of genetic and environmental information, will be required to elucidate a heritability of life-style related diseases completely. PMID:26923980

  8. Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient.

    Zondervan, Krina T; Rahmioglu, Nilufer; Morris, Andrew P; Nyholt, Dale R; Montgomery, Grant W; Becker, Christian M; Missmer, Stacey A

    2016-07-01

    Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remains unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with revised American Fertility Society stage III/IV, rather than stage I/II. The loci are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcription factor binding, epigenetic modification (e.g., DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis-in particular, endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonisation Project is a global standardization initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments. PMID:27513026

  9. SNPpy--database management for SNP data from genome wide association studies.

    Faheem Mitha

    Full Text Available BACKGROUND: We describe SNPpy, a hybrid script database system using the Python SQLAlchemy library coupled with the PostgreSQL database to manage genotype data from Genome-Wide Association Studies (GWAS. This system makes it possible to merge study data with HapMap data and merge across studies for meta-analyses, including data filtering based on the values of phenotype and Single-Nucleotide Polymorphism (SNP data. SNPpy and its dependencies are open source software. RESULTS: The current version of SNPpy offers utility functions to import genotype and annotation data from two commercial platforms. We use these to import data from two GWAS studies and the HapMap Project. We then export these individual datasets to standard data format files that can be imported into statistical software for downstream analyses. CONCLUSIONS: By leveraging the power of relational databases, SNPpy offers integrated management and manipulation of genotype and phenotype data from GWAS studies. The analysis of these studies requires merging across GWAS datasets as well as patient and marker selection. To this end, SNPpy enables the user to filter the data and output the results as standardized GWAS file formats. It does low level and flexible data validation, including validation of patient data. SNPpy is a practical and extensible solution for investigators who seek to deploy central management of their GWAS data.

  10. Genome-wide association with residual body weight gain in Bos indicus cattle.

    Santana, M H A; Gomes, R C; Utsunomiya, Y T; Neves, H H R; Novais, F J; Bonin, M N; Fukumasu, H; Garcia, J F; Alexandre, P A; Oliveira Junior, G A; Coutinho, L L; Ferraz, J B S

    2015-01-01

    Weight gain is a key performance trait for beef cat-tle; however, attention should be given to the production costs for better profitability. Therefore, a feed efficiency trait based on per-formance can be an interesting approach to improve performance without increasing food costs. To identify candidate genes and ge-nomic regions associated with residual body weight gain (RWG), we conducted a genome-wide association study (GWAS) with 720 Nellore cattle using the GRAMMAR-Gamma association test. We identified 30 significant single nucleotide polymorphisms (SNPs), especially on chromosomes 2, 8, 12, and 17. Several genes and quantitative train loci (QTLs) present in the regions identified were appointed; we highlight DMRT2 (doublesex and mab-3 related tran-scription factor 2), IFFO2 (intermediate filament family orphan 2), LNX2 (ligand of numb-protein X 2), MTIF3 (mitochondrial transla-tional initiation factor 3), and TRNAG-CCC (transfer RNA glycine anticodon CCC). The metabolic pathways that can explain part of the phenotypic variation in RWG are related to oxidative stress and muscle control. PMID:26125717

  11. Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Rose, Emma J; Morris, Derek W; Hargreaves, April; Fahey, Ciara; Greene, Ciara; Garavan, Hugh; Gill, Michael; Corvin, Aiden; Donohoe, Gary

    2013-09-01

    The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk. PMID:23839771

  12. A mega-analysis of genome-wide association studies for major depressive disorder.

    Ripke, Stephan; Wray, Naomi R; Lewis, Cathryn M; Hamilton, Steven P; Weissman, Myrna M; Breen, Gerome; Byrne, Enda M; Blackwood, Douglas H R; Boomsma, Dorret I; Cichon, Sven; Heath, Andrew C; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A F; Martin, Nicholas G; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M; Penninx, Brenda P; Pergadia, Michele L; Potash, James B; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H; Preisig, Martin; Smoller, Jordan W; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R; Bettecken, Thomas; Binder, Elisabeth B; Breuer, René; Castro, Victor M; Churchill, Susanne E; Coryell, William H; Craddock, Nick; Craig, Ian W; Czamara, Darina; De Geus, Eco J; Degenhardt, Franziska; Farmer, Anne E; Fava, Maurizio; Frank, Josef; Gainer, Vivian S; Gallagher, Patience J; Gordon, Scott D; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K; Herms, Stefan; Hickie, Ian B; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A; Kohane, Isaac S; Kohli, Martin A; Korszun, Ania; Landen, Mikael; Lawson, William B; Lewis, Glyn; Macintyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M; Middleton, Lefkos; Montgomery, Grant M; Murphy, Shawn N; Nauck, Matthias; Nolen, Willem A; Nyholt, Dale R; O'Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A; Schulz, Andrea; Schulze, Thomas G; Shyn, Stanley I; Sigurdsson, Engilbert; Slager, Susan L; Smit, Johannes H; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J C G; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B; Willemsen, Gonneke; Zitman, Frans G; Neale, Benjamin; Daly, Mark; Levinson, Douglas F; Sullivan, Patrick F

    2013-04-01

    Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with Pgenetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status. PMID:22472876

  13. Implication of the immune system in Alzheimer's disease: evidence from genome-wide pathway analysis.

    Lambert, Jean-Charles; Grenier-Boley, Benjamin; Chouraki, Vincent; Heath, Simon; Zelenika, Diana; Fievet, Nathalie; Hannequin, Didier; Pasquier, Florence; Hanon, Olivier; Brice, Alexis; Epelbaum, Jacques; Berr, Claudine; Dartigues, Jean-Francois; Tzourio, Christophe; Campion, Dominique; Lathrop, Mark; Amouyel, Philippe

    2010-01-01

    The results of several genome-wide association studies (GWASs) in the field of Alzheimer's disease (AD) have recently been published. Although these studies reported in detail on single-nucleotide polymorphisms (SNPs) and the neighboring genes with the strongest evidence of association with AD, little attention was paid to the rest of the genome. However, complementary statistical and bio-informatics approaches now enable the extraction of pertinent information from other SNPs and/or genes which are only nominally associated with the disease risk. Two different tools (the ALIGATOR and GenGen/KEGG software packages) were used to analyze a large GWAS dataset containing 2,032 AD cases and 5,328 controls. Convergent outputs from the two gene set enrichment approaches suggested an immune system dysfunction in AD. Furthermore, although these statistical approaches did not adopt a priori hypotheses concerning a biological function's putative role in the disease process, genes associated with AD risk were overrepresented in the "Alzheimer's disease" KEGG pathway. In conclusion, a systematic search for biological pathways using GWAS data set seems to comfort the primary causes already suspected but may specifically highlight the importance of the immune system in AD. PMID:20413860

  14. Epidemiological and genome-wide association study of gastritis or gastric ulcer in korean populations.

    Oh, Sumin; Oh, Sejong

    2014-09-01

    Gastritis is a major disease that has the potential to grow as gastric cancer. Gastric cancer is a very common cancer, and it is related to a very high mortality rate in Korea. This disease is known to have various reasons, including infection with Helicobacter pylori, dietary habits, tobacco, and alcohol. The incidence rate of gastritis has reported to differ between age, population, and gender. However, unlike other factors, there has been no analysis based on gender. So, we examined the high risk factors of gastritis in each gender in the Korean population by focusing on sex. We performed an analysis of 120 clinical characteristics and genome-wide association studies (GWAS) using 349,184 single-nucleotide polymorphisms from the results of Anseong and Ansan cohort study in the Korea Association Resource (KARE) project. As the result, we could not prove a strong relation with these factors and gastritis or gastric ulcer in the GWAS. However, we confirmed several already-known risk factors and also found some differences of clinical characteristics in each gender using logistic regression. As a result of the logistic regression, a relation with hyperlipidemia, coronary artery disease, myocardial infarction, hyperlipidemia therapy, hypotensive or antihypotensive drug, diastolic blood pressure, and gastritis was seen in males; the results of this study suggest that vascular disease has a potential association with gastritis in males. PMID:25317112

  15. Comparison of genome-wide variation between Malawians and African ancestry HapMap populations.

    Joubert, Bonnie R; North, Kari E; Wang, Yunfei; Mwapasa, Victor; Franceschini, Nora; Meshnick, Steven R; Lange, Ethan M

    2010-06-01

    Understanding genetic variation between populations is important because it affects the portability of human genome-wide analytical methods. We compared genetic variation and substructure between Malawians and other African and non-African HapMap populations. Allele frequencies and adjacent linkage disequilibrium (LD) were measured for 617 715 single nucleotide polymorphisms (SNPs) across subject genomes. Allele frequencies in the Malawian population (N=226) were highly correlated with allele frequencies in HapMap populations of African ancestry (AFA, N=376), namely Yoruban in Ibadan, Nigeria (Spearman's r(2)=0.97), Luhya in Webuye, Kenya (r(2)=0.97), African Americans in the southwest United States (r(2)=0.94) and Maasai in Kinyawa, Kenya (r(2)=0.91). This correlation was much lower between Malawians and other ancestry populations (r(2)0.82, other ancestries r(2)Maasai in Kenyawa, Kenya (rs3769013, rs730005, rs3769012, rs2304370; P-values <1 x 10(-33)). PMID:20485449

  16. Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep.

    Wei, Caihong; Wang, Huihua; Liu, Gang; Zhao, Fuping; Kijas, James W; Ma, Youji; Lu, Jian; Zhang, Li; Cao, Jiaxue; Wu, Mingming; Wang, Guangkai; Liu, Ruizao; Liu, Zhen; Zhang, Shuzhen; Liu, Chousheng; Du, Lixin

    2016-01-01

    Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3' untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation. PMID:27230812

  17. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.

    Kouri, Naomi; Ross, Owen A; Dombroski, Beth; Younkin, Curtis S; Serie, Daniel J; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B; Farlow, Martin R; Grafman, Jordan; Huey, Edward D; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T; Kretzschmar, Hans A; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L; Vonsattel, Jean Paul G; Van Deerlin, Vivianna M; Grossman, Murray; Hurtig, Howard I; Gross, Rachel G; Arnold, Steven E; Trojanowski, John Q; Lee, Virginia M; Wenning, Gregor K; White, Charles L; Höglinger, Günter U; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I; Crook, Julia; Parisi, Joseph E; Boeve, Bradley F; Josephs, Keith A; Wszolek, Zbigniew K; Uitti, Ryan J; Graff-Radford, Neill R; Litvan, Irene; Younkin, Steven G; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D; Dickson, Dennis W

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  18. Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Rose, Emma J

    2013-09-01

    The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk.

  19. Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Donohoe, G

    2013-03-01

    The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk \\'A\\' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk \\'A\\' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified \\'A\\' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

  20. A genome-wide scan for common alleles affecting risk for autism.

    Anney, Richard

    2010-10-15

    Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner\\'s curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

  1. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

    Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.; Farlow, Martin R.; Grafman, Jordan; Huey, Edward D.; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T.; Kretzschmar, Hans A.; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L.; Vonsattel, Jean Paul G.; Van Deerlin, Vivianna M.; Grossman, Murray; Hurtig, Howard I.; Gross, Rachel G.; Arnold, Steven E.; Trojanowski, John Q.; Lee, Virginia M.; Wenning, Gregor K.; White, Charles L.; Höglinger, Günter U.; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I.; Crook, Julia; Parisi, Joseph E.; Boeve, Bradley F.; Josephs, Keith A.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Graff-Radford, Neill R.; Litvan, Irene; Younkin, Steven G.; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D.; Dickson, Dennis W.

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  2. A genome-wide copy number variant study of suicidal behavior.

    Jeffrey A Gross

    Full Text Available Suicide and suicide attempts are complex behaviors that result from the interaction of different factors, including genetic variants that increase the predisposition to suicidal behaviors. Copy number variations (CNVs are deletions or duplications of a segment of DNA usually larger than one kilobase. These structural genetic changes, although quite rare, have been associated with genetic liability to mental disorders, such as autism, schizophrenia, and bipolar disorder. No genome-wide level studies have been published investigating the potential role of CNVs in suicidal behaviors. Based on single-nucleotide polymorphism array data, we followed the Penn-CNV standards to detect CNVs in 1,608 subjects, comprising 475 suicide and suicide attempt cases and 1,133 controls. Although the initial algorithms determined the presence of CNVs on chromosomes 6 and 12 in seven and eight cases, respectively, compared with none of the controls, visual inspection of the raw data did not support this finding. Furthermore we were unable to validate these findings by CNV-specific real-time polymerase chain reaction. Additionally, rare CNV burden analysis did not find an association between the frequency or length of rare CNVs and suicidal behavior in our sample population. Although our findings suggest CNVs do not play an important role in the etiology of suicidal behaviors, they are not inconsistent with the strong evidence from the literature suggesting that other genetic variants account for a portion of the total phenotypic variability in suicidal behavior.

  3. Genome-wide association of lipid-lowering response to statins in combined study populations.

    Mathew J Barber

    Full Text Available BACKGROUND: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs contributing to this variation, we performed a combined analysis of genome-wide association (GWA results from three trials of statin efficacy. METHODS AND PRINCIPAL FINDINGS: Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks, Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks, and Treating to New Targets (10 mg/day atorvastatin, 8 weeks. Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8. This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6. Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. CONCLUSIONS AND SIGNIFICANCE: Using combined GWA analysis from three clinical trials involving nearly 4

  4. Genome-wide association study of tick resistance in South African Nguni cattle.

    Mapholi, N O; Maiwashe, A; Matika, O; Riggio, V; Bishop, S C; MacNeil, M D; Banga, C; Taylor, J F; Dzama, K

    2016-04-01

    Ticks and tick-borne diseases are among the main causes of economic loss in the South African cattle industry through high morbidity and mortality rates. Concerns of the general public regarding chemical residues may tarnish their perceptions of food safety and environmental health when the husbandry of cattle includes frequent use of acaricides to manage ticks. The primary objective of this study was to identify single nucleotide polymorphism (SNP) markers associated with host resistance to ticks in South African Nguni cattle. Tick count data were collected monthly from 586 Nguni cattle reared in four herds under natural grazing conditions over a period of two years. The counts were recorded for six species of ticks attached in eight anatomical locations on the animals and were summed by species and anatomical location. This gave rise to 63 measured phenotypes or traits, with results for 12 of these traits being reported here. Tick count (x) data were transformed using log10(x+1) and the resulting values were examined for normality. DNA was extracted from hair and blood samples and was genotyped using the Illumina BovineSNP50 assay. After quality control (call rate >90%, minor allele frequency >0.02), 40,436 SNPs were retained for analysis. Genetic parameters were estimated and association analysis for tick resistance was carried out using two approaches: a genome-wide association (GWA) analysis using the GenABEL package and a regional heritability mapping (RHM) analysis. The Bonferroni genome-wide (Psire models ranged from 0.02±0.00 to 0.17±0.04 for the transformed tick count data. Several genomic regions harbouring quantitative trait loci (QTL) were identified for different tick count traits by both the GWA and RHM approaches. Three genome-wide significant regions on chromosomes 7, 10 and 19 were identified for total tick count on the head, total body A. hebraeum tick count and total A. hebraeum on the perineum region, respectively. Additional regions

  5. A genome-wide association study of serum uric acid in African Americans

    Gerry Norman P

    2011-02-01

    Full Text Available Abstract Background Uric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI, sex, and multiple complex diseases including gout, hypertension (HTN, renal disease, and type 2 diabetes (T2D. Multiple genome-wide association studies (GWAS in individuals of European ancestry (EA have reported associations between serum uric acid levels (SUAL and specific genomic loci. The purposes of this study were: 1 to replicate major signals reported in EA populations; and 2 to use the weak LD pattern in African ancestry population to better localize (fine-map reported loci and 3 to explore the identification of novel findings cognizant of the moderate sample size. Methods African American (AA participants (n = 1,017 from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix® Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification. Results Four variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 × 10-9 to 1.38 × 10-9. Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples. Conclusions The most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA

  6. ParallABEL: an R library for generalized parallelization of genome-wide association studies

    Tandayya Pichaya

    2010-04-01

    Full Text Available Abstract Background Genome-Wide Association (GWA analysis is a powerful method for identifying loci associated with complex traits and drug response. Parts of GWA analyses, especially those involving thousands of individuals and consuming hours to months, will benefit from parallel computation. It is arduous acquiring the necessary programming skills to correctly partition and distribute data, control and monitor tasks on clustered computers, and merge output files. Results Most components of GWA analysis can be divided into four groups based on the types of input data and statistical outputs. The first group contains statistics computed for a particular Single Nucleotide Polymorphism (SNP, or trait, such as SNP characterization statistics or association test statistics. The input data of this group includes the SNPs/traits. The second group concerns statistics characterizing an individual in a study, for example, the summary statistics of genotype quality for each sample. The input data of this group includes individuals. The third group consists of pair-wise statistics derived from analyses between each pair of individuals in the study, for example genome-wide identity-by-state or genomic kinship analyses. The input data of this group includes pairs of SNPs/traits. The final group concerns pair-wise statistics derived for pairs of SNPs, such as the linkage disequilibrium characterisation. The input data of this group includes pairs of individuals. We developed the ParallABEL library, which utilizes the Rmpi library, to parallelize these four types of computations. ParallABEL library is not only aimed at GenABEL, but may also be employed to parallelize various GWA packages in R. The data set from the North American Rheumatoid Arthritis Consortium (NARAC includes 2,062 individuals with 545,080, SNPs' genotyping, was used to measure ParallABEL performance. Almost perfect speed-up was achieved for many types of analyses. For example, the computing

  7. Genome-wide Association Study of Biochemical Traits in Korčula Island, Croatia

    Zemunik, Tatijana; Boban, Mladen; Lauc, Gordan; Janković, Stipan; Rotim, Krešimir; Vatavuk, Zoran; Benčić, Goran; Đogaš, Zoran; Boraska, Vesna; Torlak, Vesela; Sušac, Jelena; Zobić, Ivana; Rudan, Diana; Pulanić, Dražen; Modun, Darko; Mudnić, Ivana; Gunjača, Grgo; Budimir, Danijela; Hayward, Caroline; Vitart, Veronique; Wright, Alan F.; Campbell, Harry; Rudan, Igor

    2009-01-01

    Aim To identify genetic variants underlying biochemical traits – total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, albumin, and fibrinogen, in a genome-wide association study in an isolated population where rare variants of larger effect may be more easily identified. Methods The study included 944 adult inhabitants of the island of Korčula, as a part of a larger DNA-based genetic epidemiological study in 2007. Biochemical measurements were performed in a single laboratory with stringent internal and external quality control procedures. Examinees were genotyped using Human Hap370CNV chip by Illumina, with a genome-wide scan containing 346 027 single nucleotide polymorphisms (SNP). Results A total of 31 SNPs were associated with 7 investigated traits at the level of P < 1.00 × 10−5. Nine of SNPs implicated the role of SLC2A9 in uric acid regulation (P = 4.10 × 10−6-2.58 × 10−12), as previously found in other populations. All 22 remaining associations fell into the P = 1.00 × 10−5-1.00 × 10−6 significance range. One of them replicated the association between cholesteryl ester transfer protein (CETP) and HDL, and 7 associations were more than 100 kilobases away from the closest known gene. Nearby SNPs, rs4767631 and rs10444502, in gene kinase suppressor of ras 2 (KSR2) on chromosome 12 were associated with LDL cholesterol levels, and rs10444502 in the same gene with total cholesterol levels. Similarly, rs2839619 in gene PBX/knotted 1 homeobox 1 (PKNOX1) on chromosome 21 was associated with total and LDL cholesterol levels. The remaining 9 findings implied possible associations between phosphatidylethanolamine N-methyltransferase (PEMT) gene and total cholesterol; USP46, RAP1GDS1, and ZCCHC16 genes and triglycerides; BCAT1 and SLC14A2 genes and albumin; and NR3C2, GRIK2, and PCSK2 genes and fibrinogen. Conclusion Although this study was

  8. Novel Single-Nucleotide Polymorphism Markers Predictive of Pathologic Response to Preoperative Chemoradiation Therapy in Rectal Cancer Patients

    Kim, Jin C., E-mail: jckim@amc.seoul.kr [Department of Surgery, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Ha, Ye J.; Roh, Seon A. [Department of Surgery, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Cho, Dong H. [Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-do (Korea, Republic of); Choi, Eun Y. [Department of Surgery, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Kim, Tae W. [Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Department of Internal Medicine, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kim, Jong H. [Department of Radiation Oncology, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Kang, Tae W. [Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, Seon Y. [Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, Yong S., E-mail: yongsung@kribb.re.kr [Institute of Innovative Cancer Research and Asan Institute for Life Sciences, Asan Medical Center, Seoul (Korea, Republic of); Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of)

    2013-06-01

    Purpose: Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. Methods and Materials: A 3-step strategy for the determination of CRT sensitivity is proposed based on (1) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); (2) clinical association analysis of 113 patients treated with preoperative CRT; and (3) a cell-based functional assay for biological validation. Results: Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele (C) of the SNP CORO2A rs1985859 than in those with the substitution allele (T) (P=.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% (P=.048) and 39% (P=.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells (P=.034 and .015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells (P=.047), and it enhanced colony formation in RKO cells (P=.001) and COLO320DM cells (P=.002). Conclusion: CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts.

  9. Novel Single-Nucleotide Polymorphism Markers Predictive of Pathologic Response to Preoperative Chemoradiation Therapy in Rectal Cancer Patients

    Purpose: Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. Methods and Materials: A 3-step strategy for the determination of CRT sensitivity is proposed based on (1) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); (2) clinical association analysis of 113 patients treated with preoperative CRT; and (3) a cell-based functional assay for biological validation. Results: Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele (C) of the SNP CORO2A rs1985859 than in those with the substitution allele (T) (P=.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% (P=.048) and 39% (P=.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells (P=.034 and .015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells (P=.047), and it enhanced colony formation in RKO cells (P=.001) and COLO320DM cells (P=.002). Conclusion: CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts

  10. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z.; Fuchs, Charles S.; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D.; Berrino, Franco; Bingham, Sheila; Buring, Julie E.; Bracci, Paige M.; Canzian, Federico; Clavel-Chapelon, Françoise; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J.; Fox, John W.; Gallinger, Steven; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; González, Carlos A.; Hallmans, Göran; Hankinson, Susan E.; Hassan, Manal; Holly, Elizabeth A.; Hunter, David J.; Hutchinson, Amy; Jackson, Rebecca; Jacobs, Kevin B.; Jenab, Mazda; Kaaks, Rudolf; Klein, Alison P.; Kooperberg, Charles; Kurtz, Robert C.; Li, Donghui; Lynch, Shannon M.; Mandelson, Margaret; McWilliams, Robert R.; Mendelsohn, Julie B.; Michaud, Dominique S.; Olson, Sara H.; Overvad, Kim; Patel, Alpa V.; Peeters, Petra H.M.; Rajkovic, Aleksandar; Riboli, Elio; Risch, Harvey A.; Shu, Xiao-Ou; Thomas, Gilles; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K.; Virtamo, Jarmo; Wactawski-Wende, Jean; Wolpin, Brian M.; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Chanock, Stephen J.; Hartge, Patricia; Hoover, Robert N.

    2010-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-control studies, we identified an association between a locus on 9q34 and pancreatic cancer marked by the single nucleotide polymorphism, rs505922 (combined P=5.37 × 10-8; multiplicative per-allele odds ratio (OR) 1.20; 95% CI 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B. PMID:19648918

  11. Genome-wide association analysis of ten chilling tolerance indices at the germination and seedling stages in maize.

    Huang, Juan; Zhang, Jianhua; Li, Wenzhen; Hu, Wei; Duan, Lichao; Feng, Yang; Qiu, Fazhan; Yue, Bing

    2013-08-01

    Maize seedlings are very sensitive to chilling, especially during the transition phase from heterotrophic to autotrophic growth. Genetic dissection of the genetic basis of chilling tolerance would provide useful information for genetic improvement of maize inbreds. In this study, genome-wide association analysis was conducted to explore the genetic architecture of maize chilling tolerance at the seed germination and seedling stages with an association panel of 125 inbreds. Ten tolerance indices (ratios of the performance of 10 germination rates and seedling growth-related traits under chilling stress and control conditions) were investigated to assess the ability of chilling tolerance of the inbreds, and a total of 43 single nucleotide polymorphisms associated with chilling tolerance were detected, with none of them being related to chilling tolerance at both the germination and seedling stages simultaneously. Correlation analysis also revealed that the genetic basis of chilling tolerance at the seed germination stage is generally different from that at the seedling stage. In addition, a total of 40 candidate genes involving 31 of the 43 single nucleotide polymorphisms were predicted, and were grouped into five categories according to their functions. The possible roles of these candidate genes in chilling tolerance were also discussed. PMID:23551400

  12. Genome-wide Association Analysis of Ten Chilling Tolerance Indices at the Germination and Seedling Stages in Maize

    Juan Huang; Jianhua Zhang; Wenzhen Li; Wei Hu; Lichao Duan; Yang Feng; Fazhan Qiu

    2013-01-01

    Maize seedlings are very sensitive to chilling,especially during the transition phase from heterotrophic to autotrophic growth.Genetic dissection of the genetic basis of chilling tolerance would provide useful information for genetic improvement of maize inbreds.In this study,genome-wide association analysis was conducted to explore the genetic architecture of maize chilling tolerance at the seed germination and seedling stages with an association panel of 125 inbreds.Ten tolerance indices (ratios of the performance of 10 germination rates and seedling growth-related traits under chilling stress and control conditions)were investigated to assess the ability of chilling tolerance of the inbreds,and a total of 43 single nucleotide polymorphisms associated with chilling tolerance were detected,with none of them being related to chilling tolerance at both the germination and seedling stages simultaneously.Correlation analysis also revealed that the genetic basis of chilling tolerance at the seed germination stage is generally different from that at the seedling stage.In addition,a total of 40 candidate genes involving 31 of the 43 single nucleotide polymorphisms were predicted,and were grouped into five categories according to their functions.The possible roles of these candidate genes in chilling tolerance were also discussed.

  13. A Transcriptome Map of Actinobacillus pleuropneumoniae at Single-Nucleotide Resolution Using Deep RNA-Seq

    Su, Zhipeng; Zhu, Jiawen; Xu, Zhuofei; Xiao, Ran; Zhou, Rui; Li, Lu; Chen, Huanchun

    2016-01-01

    Actinobacillus pleuropneumoniae is the pathogen of porcine contagious pleuropneumoniae, a highly contagious respiratory disease of swine. Although the genome of A. pleuropneumoniae was sequenced several years ago, limited information is available on the genome-wide transcriptional analysis to accurately annotate the gene structures and regulatory elements. High-throughput RNA sequencing (RNA-seq) has been applied to study the transcriptional landscape of bacteria, which can efficiently and accurately identify gene expression regions and unknown transcriptional units, especially small non-coding RNAs (sRNAs), UTRs and regulatory regions. The aim of this study is to comprehensively analyze the transcriptome of A. pleuropneumoniae by RNA-seq in order to improve the existing genome annotation and promote our understanding of A. pleuropneumoniae gene structures and RNA-based regulation. In this study, we utilized RNA-seq to construct a single nucleotide resolution transcriptome map of A. pleuropneumoniae. More than 3.8 million high-quality reads (average length ~90 bp) from a cDNA library were generated and aligned to the reference genome. We identified 32 open reading frames encoding novel proteins that were mis-annotated in the previous genome annotations. The start sites for 35 genes based on the current genome annotation were corrected. Furthermore, 51 sRNAs in the A. pleuropneumoniae genome were discovered, of which 40 sRNAs were never reported in previous studies. The transcriptome map also enabled visualization of 5'- and 3'-UTR regions, in which contained 11 sRNAs. In addition, 351 operons covering 1230 genes throughout the whole genome were identified. The RNA-Seq based transcriptome map validated annotated genes and corrected annotations of open reading frames in the genome, and led to the identification of many functional elements (e.g. regions encoding novel proteins, non-coding sRNAs and operon structures). The transcriptional units described in this study

  14. A novel statistic for genome-wide interaction analysis.

    Xuesen Wu

    2010-09-01

    Full Text Available Although great progress in genome-wide association studies (GWAS has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked. The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  15. Myosin individualized: single nucleotide polymorphisms in energy transduction

    Wieben Eric D

    2010-03-01

    Full Text Available Abstract Background Myosin performs ATP free energy transduction into mechanical work in the motor domain of the myosin heavy chain (MHC. Energy transduction is the definitive systemic feature of the myosin motor performed by coordinating in a time ordered sequence: ATP hydrolysis at the active site, actin affinity modulation at the actin binding site, and the lever-arm rotation of the power stroke. These functions are carried out by several conserved sub-domains within the motor domain. Single nucleotide polymorphisms (SNPs affect the MHC sequence of many isoforms expressed in striated muscle, smooth muscle, and non-muscle tissue. The purpose of this work is to provide a rationale for using SNPs as a functional genomics tool to investigate structurefunction relationships in myosin. In particular, to discover SNP distribution over the conserved sub-domains and surmise what it implies about sub-domain stability and criticality in the energy transduction mechanism. Results An automated routine identifying human nonsynonymous SNP amino acid missense substitutions for any MHC gene mined the NCBI SNP data base. The routine tested 22 MHC genes coding muscle and non-muscle isoforms and identified 89 missense mutation positions in the motor domain with 10 already implicated in heart disease and another 8 lacking sequence homology with a skeletal MHC isoform for which a crystallographic model is available. The remaining 71 SNP substitutions were found to be distributed over MHC with 22 falling outside identified functional sub-domains and 49 in or very near to myosin sub-domains assigned specific crucial functions in energy transduction. The latter includes the active site, the actin binding site, the rigid lever-arm, and regions facilitating their communication. Most MHC isoforms contained SNPs somewhere in the motor domain. Conclusions Several functional-crucial sub-domains are infiltrated by a large number of SNP substitution sites suggesting these

  16. Genome-wide association study identifies five new schizophrenia loci

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A; Scolnick, Edward; Cichon, Sven; St. Clair, David; Corvin, Aiden; Gurling, Hugh

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated ...

  17. Genome-wide association study identifies five new schizophrenia loci.

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A; Scolnick, Edward; Cichon, Sven; St. Clair, David; Corvin, Aiden; Gurling, Hugh

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated ...

  18. Use of stochastic simulations to investigate the power and design of a whole genome association study using single nucleotide

    2007-01-01

    This paper presents a quick, easy to implement and versatile way of using stochastic simulations to investigate the power and design of using single nucleotide polymorphism (SNP) arrays for genome-wide association studies in farm animals. It illustrates the methodology by discussing a small example where 6 experimental designs are considered to analyse the same resource consisting of 6006 animals with pedigree and phenotypic records: (1) genotyping the 30 most widely used sires in the population and all of their progeny (515 animals in total), (2) genotyping the 100 most widely used sires in the population and all of their progeny (1 102 animals in total), genotyping respectively (3) 515 and (4) 1 102 animals selected randomly or genotyping respectively (5) 515 and (6) 1 102 animals from the tails of the phenotypic distribution. Given the resource at hand, designs where the extreme animals are genotyped perform the best, followed by designs selecting animals at random. Designs where sires and their progeny are genotyped perform the worst, as even genotyping the 100 most widely used sires and their progeny is not as powerful of genotyping 515 extreme animals.

  19. Analysis of the genotype of diacylglycerol kinase delta single-nucleotide polymorphisms in Parkinson disease in the Han Chinese population

    Wei Song

    2012-01-01

    Full Text Available Numerous Single-Nucleotide Polymorphisms (SNPs of the Diacylglycerol Kinase Delta (DGKD isoform 1 gene have been associated with Parkinson Disease (PD in the genome-wide association studies of Caucasian population. This association has not been proven in the Han Chinese PD patients. This study included 376 unrelated Han Chinese PD patients from West China and 273 unrelated healthy controls from the same region. Five SNPs (rs2971859, rs1550532, rs2305539, rs2034762, and rs2242102 were genotyped using the Sequenom iPLEX Assay technology. No significant differences were observed in genotype frequencies and in the Minor Allele Frequency (MAF in the five SNPs between PD patients and controls, early-onset PD and controls, late-onset PD and controls, and between early-onset and late-onset PD patients. The present study is the first to report on the lack of association of DGKD SNPs with PD in the Han Chinese population. More related studies involving larger numbers of participants are necessary to confirm the present finding.

  20. Genome-Wide Association Mapping and Genomic Prediction Elucidate the Genetic Architecture of Morphological Traits in Arabidopsis.

    Kooke, Rik; Kruijer, Willem; Bours, Ralph; Becker, Frank; Kuhn, André; van de Geest, Henri; Buntjer, Jaap; Doeswijk, Timo; Guerra, José; Bouwmeester, Harro; Vreugdenhil, Dick; Keurentjes, Joost J B

    2016-04-01

    Quantitative traits in plants are controlled by a large number of genes and their interaction with the environment. To disentangle the genetic architecture of such traits, natural variation within species can be explored by studying genotype-phenotype relationships. Genome-wide association studies that link phenotypes to thousands of single nucleotide polymorphism markers are nowadays common practice for such analyses. In many cases, however, the identified individual loci cannot fully explain the heritability estimates, suggesting missing heritability. We analyzed 349 Arabidopsis accessions and found extensive variation and high heritabilities for different morphological traits. The number of significant genome-wide associations was, however, very low. The application of genomic prediction models that take into account the effects of all individual loci may greatly enhance the elucidation of the genetic architecture of quantitative traits in plants. Here, genomic prediction models revealed different genetic architectures for the morphological traits. Integrating genomic prediction and association mapping enabled the assignment of many plausible candidate genes explaining the observed variation. These genes were analyzed for functional and sequence diversity, and good indications that natural allelic variation in many of these genes contributes to phenotypic variation were obtained. For ACS11, an ethylene biosynthesis gene, haplotype differences explaining variation in the ratio of petiole and leaf length could be identified. PMID:26869705

  1. MegaSNPHunter: a learning approach to detect disease predisposition SNPs and high level interactions in genome wide association study

    Xue Hong

    2009-01-01

    Full Text Available Abstract Background The interactions of multiple single nucleotide polymorphisms (SNPs are highly hypothesized to affect an individual's susceptibility to complex diseases. Although many works have been done to identify and quantify the importance of multi-SNP interactions, few of them could handle the genome wide data due to the combinatorial explosive search space and the difficulty to statistically evaluate the high-order interactions given limited samples. Results Three comparative experiments are designed to evaluate the performance of MegaSNPHunter. The first experiment uses synthetic data generated on the basis of epistasis models. The second one uses a genome wide study on Parkinson disease (data acquired by using Illumina HumanHap300 SNP chips. The third one chooses the rheumatoid arthritis study from Wellcome Trust Case Control Consortium (WTCCC using Affymetrix GeneChip 500K Mapping Array Set. MegaSNPHunter outperforms the best solution in this area and reports many potential interactions for the two real studies. Conclusion The experimental results on both synthetic data and two real data sets demonstrate that our proposed approach outperforms the best solution that is currently available in handling large-scale SNP data both in terms of speed and in terms of detection of potential interactions that were not identified before. To our knowledge, MegaSNPHunter is the first approach that is capable of identifying the disease-associated SNP interactions from WTCCC studies and is promising for practical disease prognosis.

  2. Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.

    Wray, N R; Pergadia, M L; Blackwood, D H R; Penninx, B W J H; Gordon, S D; Nyholt, D R; Ripke, S; MacIntyre, D J; McGhee, K A; Maclean, A W; Smit, J H; Hottenga, J J; Willemsen, G; Middeldorp, C M; de Geus, E J C; Lewis, C M; McGuffin, P; Hickie, I B; van den Oord, E J C G; Liu, J Z; Macgregor, S; McEvoy, B P; Byrne, E M; Medland, S E; Statham, D J; Henders, A K; Heath, A C; Montgomery, G W; Martin, N G; Boomsma, D I; Madden, P A F; Sullivan, P F

    2012-01-01

    Major depressive disorder (MDD) is a common complex disorder with a partly genetic etiology. We conducted a genome-wide association study of the MDD2000+ sample (2431 cases, 3673 screened controls and >1 M imputed single-nucleotide polymorphisms (SNPs)). No SNPs achieved genome-wide significance either in the MDD2000+ study, or in meta-analysis with two other studies totaling 5763 cases and 6901 controls. These results imply that common variants of intermediate or large effect do not have main effects in the genetic architecture of MDD. Suggestive but notable results were (a) gene-based tests suggesting roles for adenylate cyclase 3 (ADCY3, 2p23.3) and galanin (GAL, 11q13.3); published functional evidence relates both of these to MDD and serotonergic signaling; (b) support for the bipolar disorder risk variant SNP rs1006737 in CACNA1C (P=0.020, odds ratio=1.10); and (c) lack of support for rs2251219, a SNP identified in a meta-analysis of affective disorder studies (P=0.51). We estimate that sample sizes 1.8- to 2.4-fold greater are needed for association studies of MDD compared with those for schizophrenia to detect variants that explain the same proportion of total variance in liability. Larger study cohorts characterized for genetic and environmental risk factors accumulated prospectively are likely to be needed to dissect more fully the etiology of MDD. PMID:21042317

  3. Genome-wide association analyses reveal complex genetic architecture underlying natural variation for flowering time in canola.

    Raman, H; Raman, R; Coombes, N; Song, J; Prangnell, R; Bandaranayake, C; Tahira, R; Sundaramoorthi, V; Killian, A; Meng, J; Dennis, E S; Balasubramanian, S

    2016-06-01

    Optimum flowering time is the key to maximize canola production in order to meet global demand of vegetable oil, biodiesel and canola-meal. We reveal extensive variation in flowering time across diverse genotypes of canola under field, glasshouse and controlled environmental conditions. We conduct a genome-wide association study and identify 69 single nucleotide polymorphism (SNP) markers associated with flowering time, which are repeatedly detected across experiments. Several associated SNPs occur in clusters across the canola genome; seven of them were detected within 20 Kb regions of a priori candidate genes; FLOWERING LOCUS T, FRUITFUL, FLOWERING LOCUS C, CONSTANS, FRIGIDA, PHYTOCHROME B and an additional five SNPs were localized within 14 Kb of a previously identified quantitative trait loci for flowering time. Expression analyses showed that among FLC paralogs, BnFLC.A2 accounts for ~23% of natural variation in diverse accessions. Genome-wide association analysis for FLC expression levels mapped not only BnFLC.C2 but also other loci that contribute to variation in FLC expression. In addition to revealing the complex genetic architecture of flowering time variation, we demonstrate that the identified SNPs can be modelled to predict flowering time in diverse canola germplasm accurately and hence are suitable for genomic selection of adaptative traits in canola improvement programmes. PMID:26428711

  4. Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

    Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Kühn, Christa; Schwerin, Manfred

    2016-02-01

    Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais × German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. PMID:26515756

  5. Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation

    Tsai, Chia-Ti; Hsieh, Chia-Shan; Chang, Sheng-Nan; Chuang, Eric Y.; Ueng, Kwo-Chang; Tsai, Chin-Feng; Lin, Tsung-Hsien; Wu, Cho-Kai; Lee, Jen-Kuang; Lin, Lian-Yu; Wang, Yi-Chih; Yu, Chih-Chieh; Lai, Ling-Ping; Tseng, Chuen-Den; Hwang, Juey-Jen; Chiang, Fu-Tien; Lin, Jiunn-Lee

    2016-01-01

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome-wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio=2.27 for insertion allele; P=6.23 × 10−24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway. PMID:26831368

  6. A genome-wide survey reveals a deletion polymorphism associated with resistance to gastrointestinal nematodes in Angus cattle.

    Xu, Lingyang; Hou, Yali; Bickhart, Derek M; Song, Jiuzhou; Van Tassell, Curtis P; Sonstegard, Tad S; Liu, George E

    2014-06-01

    Gastrointestinal (GI) nematode infections are a worldwide threat to human health and animal production. In this study, we performed a genome-wide association study between copy number variations (CNVs) and resistance to GI nematodes in an Angus cattle population. Using a linear regression analysis, we identified one deletion CNV which reaches genome-wide significance after Bonferroni correction. With multiple mapped human olfactory receptor genes but no annotated bovine genes in the region, this significantly associated CNV displays high population frequencies (58.26 %) with a length of 104.8 kb on chr7. We further investigated the linkage disequilibrium (LD) relationships between this CNV and its nearby single nucleotide polymorphisms (SNPs) and genes. The underlining haplotype blocks contain immune-related genes such as ZNF496 and NLRP3. As this CNV co-segregates with linked SNPs and associated genes, we suspect that it could contribute to the detected variations in gene expression and thus differences in host parasite resistance. PMID:24718732

  7. Genome-wide association study identifies five new schizophrenia loci

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S;

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis...

  8. Genome-wide characterization of maize miRNA genes

    MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in plant growth and development. We conducted a genome-wide survey of maize miRNA genes, characterizing their structure, expression, and evolution. Computational approaches based on homology and secondary structure modeling ident...

  9. An AFLP-based genome-wide mapping strategy.

    Peters, J.L.; Cnops, G.; Neyt, P.; Zethof, J.; Cornelis, K.; Lijsebettens, M. van; Gerats, A.G.M.

    2004-01-01

    To efficiently determine the chromosomal location of phenotypic mutants, we designed a genome-wide mapping strategy that can be used in any crop for which a dense AFLP (Amplified Fragment Length Polymorphism) map is available or can be made. The AFLP technique is particularly suitable to initiate ma

  10. Genome-wide association study identifies five new schizophrenia loci

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S;

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yiel...

  11. Genome-wide association mapping of soybean aphid resistance traits

    Soybean aphid is the most damaging insect pest of soybean in the Upper Midwest and is primarily controlled by insecticides. Soybean aphid resistance (i.e., Rag genes) has been documented in some soybean lines at chromosomes 6, 7, 13, and 16, but more sources of resistance are needed. Genome-wide ass...

  12. Genome-wide association study identifies five new schizophrenia loci.

    Ripke, Stephan

    2011-10-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

  13. The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.

    Elisabeth M van Leeuwen

    Full Text Available Genome-wide association studies (GWAS have revealed 74 single nucleotide polymorphisms (SNPs associated with high-density lipoprotein cholesterol (HDL blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS cohort I (RS-I using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III, we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011 when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098 and rs12442098 in SPATA8 (ENSG00000185594 being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

  14. Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients

    Zhao Linlu

    2012-06-01

    Full Text Available Abstract Background Specific genetic contributions for preeclampsia (PE are currently unknown. This genome-wide association study (GWAS aims to identify maternal single nucleotide polymorphisms (SNPs and copy-number variants (CNVs involved in the etiology of PE. Methods A genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR. Results The top four SNP candidates had an allelic or genotypic p-value between 10-5 and 10-6, however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls, which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed. Conclusions CNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.

  15. A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis.

    Dahlqvist, Johanna; Klar, Joakim; Tiwari, Neha; Schuster, Jens; Törmä, Hans; Badhai, Jitendra; Pujol, Ramon; van Steensel, Maurice A M; Brinkhuizen, Tjinta; Brinkhuijzen, Tjinta; Gijezen, Lieke; Chaves, Antonio; Tadini, Gianluca; Vahlquist, Anders; Dahl, Niklas

    2010-04-01

    KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis. PMID:20226437

  16. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

    Smith, D J; Escott-Price, V; Davies, G; Bailey, M E S; Colodro-Conde, L; Ward, J; Vedernikov, A; Marioni, R; Cullen, B; Lyall, D; Hagenaars, S P; Liewald, D C M; Luciano, M; Gale, C R; Ritchie, S J; Hayward, C; Nicholl, B; Bulik-Sullivan, B; Adams, M; Couvy-Duchesne, B; Graham, N; Mackay, D; Evans, J; Smith, B H; Porteous, D J; Medland, S E; Martin, N G; Holmans, P; McIntosh, A M; Pell, J P; Deary, I J; O'Donovan, M C

    2016-06-01

    Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured

  17. A genome-wide association study of pulmonary function measures in the Framingham Heart Study.

    Jemma B Wilk

    2009-03-01

    Full Text Available The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1/FVC is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs associated with the FEV(1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09. One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1/FVC (p-value = 2.0e-04. The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G associated with higher FEV(1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.

  18. Genome-wide association study for T lymphocyte subpopulations in swine

    Lu Xin

    2012-09-01

    Full Text Available Abstract Background Lymphocytes act as a major component of the adaptive immune system, taking very crucial responsibility for immunity. Differences in proportions of T-cell subpopulations in peripheral blood among individuals under same conditions provide evidence of genetic control on these traits, but little is known about the genetic mechanism of them, especially in swine. Identification of the genetic control on these variants may help the genetic improvement of immune capacity through selection. Results To identify genomic regions responsible for these immune traits in swine, a genome-wide association study was conducted. A total of 675 pigs of three breeds were involved in the study. At 21 days of age, all individuals were vaccinated with modified live classical swine fever vaccine. Blood samples were collected when the piglets were 20 and 35 days of age, respectively. Seven traits, including the proportions of CD4+, CD8+, CD4+CD8+, CD4+CD8−, CD4−CD8+, CD4−CD8− and the ratio of CD4+ to CD8+ T cells were measured at the two ages. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP using the Illumina porcineSNP60k BeadChip. 40833 SNPs were selected after quality control for association tests between SNPs and each immune trait considered based on a single-locus regression model. To tackle the issue of multiple testing in GWAS, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance levels of association tests. In total, 61 SNPs with chromosome-wise significance level and 3 SNPs with genome-wise significance level were identified. 27 significant SNPs were located within the immune-related QTL regions reported in previous studies. Furthermore, several significant SNPs fell into the regions harboring known immunity-related genes, 14 of them fell into the regions which harbor some known T cell-related genes. Conclusions Our study demonstrated that genome-wide association

  19. VIGoR: Variational Bayesian Inference for Genome-Wide Regression

    Onogi, Akio; Iwata, Hiroyoshi

    2016-01-01

    Genome-wide regression using a number of genome-wide markers as predictors is now widely used for genome-wide association mapping and genomic prediction. We developed novel software for genome-wide regression which we named VIGoR (variational Bayesian inference for genome-wide regression). Variational Bayesian inference is computationally much faster than widely used Markov chain Monte Carlo algorithms. VIGoR implements seven regression methods, and is provided as a command line program packa...

  20. No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.

    Jens Baumert

    Full Text Available Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI. Genome-wide association studies (GWAS have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 × 10(-8. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

  1. Genome-wide patterns of selection in 230 ancient Eurasians

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R.; Llamas, Bastien; Dryomov, Stanislav; Pickrel, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vayacheslav; Rojo Guerra, Manuel A.; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W.; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2016-01-01

    Ancient DNA makes it possible to directly witness natural selection by analyzing samples from populations before, during and after adaptation events. Here we report the first scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture whose genetic material we extracted from the DNA-rich petrous bone and who we show were members of the population that was the source of Europe’s first farmers. We also report a complete transect of the steppe region in Samara between 5500 and 1200 BCE that allows us to recognize admixture from at least two external sources into steppe populations during this period. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  2. Genome-Wide Studies of Specific Language Impairment

    Reader, Rose H.; Covill, Laura E; Nudel, Ron; Newbury, Dianne F

    2014-01-01

    Specific language impairment (SLI) is a multifactorial neurodevelopmental disorder which occurs unexpectedly and without an obvious cause. Over a decade of research suggests that SLI is highly heritable. Several genes and loci have already been implicated in SLI through linkage and targeted association methods. Recently, genome-wide association studies (GWAS) of SLI and language traits in the general population have been reported and, consequently, new candidate genes have been identified. Th...

  3. A genome-wide association study of anorexia nervosa

    2014-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were...

  4. Genome-wide Association Study of Periodontal Pathogen Colonization

    Divaris, K.; Monda, K.L.; North, K. E.; Olshan, A F; Lange, E.M.; K. Moss; Barros, S.P.; Beck, J.D.; Offenbacher, S.

    2012-01-01

    Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom “checkerboard” DNA-DNA hybridization quantifi...

  5. A genome-wide scan for preeclampsia in the Netherlands.

    Lachmeijer, A M; Arngrímsson, R; Bastiaans, E J; Frigge, M L; Pals, G; Sigurdardóttir, S; Stéfansson, H; Pálsson, B; Nicolae, D; Kong, A; Aarnoudse, J G; Gulcher, J R; Dekker, G A; ten Kate, L P; Stéfansson, K

    2001-10-01

    Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia. PMID:11781687

  6. Genome-wide association study of circulating retinol levels

    Mondul, Alison M.; Yu, Kai; Wheeler, William; Zhang, Hong; Weinstein, Stephanie J.; Major, Jacqueline M.; Cornelis, Marilyn C; Männistö, Satu; Hazra, Aditi; Hsing, Ann W.; Jacobs, Kevin B.; Eliassen, Heather; Tanaka, Toshiko; Reding, Douglas J.; Hendrickson, Sara

    2011-01-01

    Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucl...

  7. GWAMA: software for genome-wide association meta-analysis

    Mägi Reedik; Morris Andrew P

    2010-01-01

    Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages in...

  8. Genome-Wide Association Study of Proneness to Anger

    Mick, Eric; Mcgough, James,; Deutsch, Curtis K.; Jean A. Frazier; Kennedy, David; Goldberg, Robert J.

    2014-01-01

    Background Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. Methods With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger S...

  9. Sequence motif discovery with computational genome-wide analysis

    Akashi, Hirofumi; Aoki, Fumio; Toyota, Minoru; Maruyama, Reo; Sasaki, Yasushi; Mita, Hiroaki; Tokura, Hajime; Imai, Kohzoh; Tatsumi, Haruyuki

    2006-01-01

    As a result of the human genome project and advancements in DNA sequencing technology, we can utilize a huge amount of nucleotide sequence data and can search DNA sequence motifs in whole human genome. However, searching motifs with the naked eye is an enormous task and searching throughout the whole genome is absolutely impossible. Therefore, we have developed a computational genome-wide analyzing system for detecting DNA sequence motifs with biological significance. We used a multi-parallel...

  10. Patterns of Genome-Wide Variation in Glossina fuscipes fuscipes Tsetse Flies from Uganda

    Andrea Gloria-Soria

    2016-06-01

    Full Text Available The tsetse fly Glossina fuscipes fuscipes (Gff is the insect vector of the two forms of Human African Trypanosomiasis (HAT that exist in Uganda. Understanding Gff population dynamics, and the underlying genetics of epidemiologically relevant phenotypes is key to reducing disease transmission. Using ddRAD sequence technology, complemented with whole-genome sequencing, we developed a panel of ∼73,000 single-nucleotide polymorphisms (SNPs distributed across the Gff genome that can be used for population genomics and to perform genome-wide-association studies. We used these markers to estimate genomic patterns of linkage disequilibrium (LD in Gff, and used the information, in combination with outlier-locus detection tests, to identify candidate regions of the genome under selection. LD in individual populations decays to half of its maximum value (r2max/2 between 1359 and 2429 bp. The overall LD estimated for the species reaches r2max/2 at 708 bp, an order of magnitude slower than in Drosophila. Using 53 infected (Trypanosoma spp. and uninfected flies from four genetically distinct Ugandan populations adapted to different environmental conditions, we were able to identify SNPs associated with the infection status of the fly and local environmental adaptation. The extent of LD in Gff likely facilitated the detection of loci under selection, despite the small sample size. Furthermore, it is probable that LD in the regions identified is much higher than the average genomic LD due to strong selection. Our results show that even modest sample sizes can reveal significant genetic associations in this species, which has implications for future studies given the difficulties of collecting field specimens with contrasting phenotypes for association analysis.

  11. Prediction of disease and phenotype associations from genome-wide association studies.

    Stephanie N Lewis

    Full Text Available BACKGROUND: Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. METHODOLOGY/PRINCIPAL FINDINGS: Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. CONCLUSIONS/SIGNIFICANCE: The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

  12. Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster.

    Allison L Weber

    Full Text Available BACKGROUND: Aerobic organisms are susceptible to damage by reactive oxygen species. Oxidative stress resistance is a quantitative trait with population variation attributable to the interplay between genetic and environmental factors. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress. METHODS AND FINDINGS: We used 167 wild-derived inbred lines of the Drosophila Genetic Reference Panel for a genome-wide association study of acute oxidative stress resistance to two oxidizing agents, paraquat and menadione sodium bisulfite. We found significant genetic variation for both stressors. Single nucleotide polymorphisms (SNPs associated with variation in oxidative stress resistance were often sex-specific and agent-dependent, with a small subset common for both sexes or treatments. Associated SNPs had moderately large effects, with an inverse relationship between effect size and allele frequency. Linear models with up to 12 SNPs explained 67-79% and 56-66% of the phenotypic variance for resistance to paraquat and menadione sodium bisulfite, respectively. Many genes implicated were novel with no known role in oxidative stress resistance. Bioinformatics analyses revealed a cellular network comprising DNA metabolism and neuronal development, consistent with targets of oxidative stress-inducing agents. We confirmed associations of seven candidate genes associated with natural variation in oxidative stress resistance through mutational analysis. CONCLUSIONS: We identified novel candidate genes associated with variation in resistance to oxidative stress that have context-dependent effects. These results form the basis for future translational studies to identify oxidative stress susceptibility/resistance genes that are evolutionary conserved and might play a role in human disease.

  13. Genome-wide identification of genetic determinants for the cytotoxicity of perifosine

    Zhang Wei

    2008-09-01

    Full Text Available Abstract Perifosine belongs to the class of alkylphospholipid analogues, which act primarily at the cell membrane, thereby targeting signal transduction pathways. In phase I/II clinical trials, perifosine has induced tumour regression and caused disease stabilisation in a variety of tumour types. The genetic determinants responsible for its cytotoxicity have not been comprehensively studied, however. We performed a genome-wide analysis to identify genes whose expression levels or genotypic variation were correlated with the cytotoxicity of perifosine, using public databases on the US National Cancer Institute (NCI-60 human cancer cell lines. For demonstrating drug specificity, the NCI Standard Agent Database (including 171 drugs acting through a variety of mechanisms was used as a control. We identified agents with similar cytotoxicity profiles to that of perifosine in compounds used in the NCI drug screen. Furthermore, Gene Ontology and pathway analyses were carried out on genes more likely to be perifosine specific. The results suggested that genes correlated with perifosine cytotoxicity are connected by certain known pathways that lead to the mitogen-activated protein kinase signalling pathway and apoptosis. Biological processes such as 'response to stress', 'inflammatory response' and 'ubiquitin cycle' were enriched among these genes. Three single nucleotide polymorphisms (SNPs located in CACNA2DI and EXOC4 were found to be correlated with perifosine cytotoxicity. Our results provided a manageable list of genes whose expression levels or genotypic variation were strongly correlated with the cytotoxcity of perifosine. These genes could be targets for further studies using candidate-gene approaches. The results also provided insights into the pharmacodynamics of perifosine.

  14. Marker-trait associations in Virginia Tech winter barley identified using genome-wide mapping.

    Berger, Gregory L; Liu, Shuyu; Hall, Marla D; Brooks, Wynse S; Chao, Shiaoman; Muehlbauer, Gary J; Baik, B-K; Steffenson, Brian; Griffey, Carl A

    2013-03-01

    Genome-wide association studies (GWAS) provide an opportunity to examine the genetic architecture of quantitatively inherited traits in breeding populations. The objectives of this study were to use GWAS to identify chromosome regions governing traits of importance in six-rowed winter barley (Hordeum vulgare L.) germplasm and to identify single-nucleotide polymorphisms (SNPs) markers that can be implemented in a marker-assisted breeding program. Advanced hulled and hulless lines (329 total) were screened using 3,072 SNPs as a part of the US. Barley Coordinated Agricultural Project (CAP). Phenotypic data collected over 4 years for agronomic and food quality traits and resistance to leaf rust (caused by Puccinia hordei G. Otth), powdery mildew [caused by Blumeria graminis (DC.) E.O. Speer f. sp. hordei Em. Marchal], net blotch (caused by Pyrenophora teres), and spot blotch [caused by Cochliobolus sativus (Ito and Kuribayashi) Drechsler ex Dastur] were analyzed with SNP genotypic data in a GWAS to determine marker-trait associations. Significant SNPs associated with previously described quantitative trait loci (QTL) or genes were identified for heading date on chromosome 3H, test weight on 2H, yield on 7H, grain protein on 5H, polyphenol oxidase activity on 2H and resistance to leaf rust on 2H and 3H, powdery mildew on 1H, 2H and 4H, net blotch on 5H, and spot blotch on 7H. Novel QTL also were identified for agronomic, quality, and disease resistance traits. These SNP-trait associations provide the opportunity to directly select for QTL contributing to multiple traits in breeding programs. PMID:23139143

  15. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. PMID:25288136

  16. Explorations in genome-wide association studies and network analyses with dairy cattle fertility traits.

    Parker Gaddis, K L; Null, D J; Cole, J B

    2016-08-01

    The objective of this study was to identify single nucleotide polymorphisms and gene networks associated with 3 fertility traits in dairy cattle-daughter pregnancy rate, heifer conception rate, and cow conception rate-using different approaches. Deregressed predicted transmitting abilities were available for approximately 24,000 Holstein bulls and 36,000 Holstein cows sampled from the National Dairy Database with high-density genotypes. Of those, 1,732 bulls and 375 cows had been genotyped with the Illumina BovineHD Genotyping BeadChip (Illumina Inc., San Diego, CA). The remaining animals were genotyped with various chips of lower density that were imputed to high density. Univariate and trivariate genome-wide association studies (GWAS) with both medium- (60,671 markers) and high-density (312,614 markers) panels were performed for daughter pregnancy rate, heifer conception rate, and cow conception rate using GEMMA (version 0.94; http://www.xzlab.org/software.html). Analyses were conducted using bulls only, cows only, and a sample of both bulls and cows. The partial correlation and information theory algorithm was used to develop gene interaction networks. The most significant markers were further investigated to identify putatively associated genes. Little overlap in associated genes could be found between GWAS using different reference populations of bulls only, cows only, and combined bulls and cows. The partial correlation and information theory algorithm was able to identify several genes that were not identified by ordinary GWAS. The results obtained herein will aid in further dissecting the complex biology underlying fertility traits in dairy cattle, while also providing insight into the nuances of GWAS. PMID:27209127

  17. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

    Jason P Wendler

    Full Text Available BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  18. Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.

    Liu, Pengyuan; Lu, Yan; Liu, Hongbo; Wen, Weidong; Jia, Dongmei; Wang, Yian; You, Ming

    2012-01-01

    To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. PMID:22127497

  19. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. PMID:26743605

  20. Genome-Wide Association Study on Male Genital Shape and Size in Drosophila melanogaster.

    Baku Takahara

    Full Text Available Male genital morphology of animals with internal fertilization and promiscuous mating systems have been one of the most diverse and rapidly evolving morphological traits. The male genital morphology in general is known to have low phenotypic and genetic variations, but the genetic basis of the male genital variation remains unclear. Drosophila melanogaster and its closely related species are morphologically very similar, but the shapes of the posterior lobe, a cuticular projection on the male genital arch are distinct from each other, representing a model system for studying the genetic basis of male genital morphology. In this study, we used highly inbred whole genome sequenced strains of D. melanogaster to perform genome wide association analysis on posterior lobe morphology. We quantified the outline shape of posterior lobes with Fourier coefficients obtained from elliptic Fourier analysis and performed principal component analysis, and posterior lobe size. The first and second principal components (PC1 and PC2 explained approximately 88% of the total variation of the posterior lobe shape. We then examined the association between the principal component scores and posterior lobe size and 1902142 single nucleotide polymorphisms (SNPs. As a result, we obtained 15, 14 and 15 SNPs for PC1, PC2 and posterior lobe size with P-values smaller than 10(-5. Based on the location of the SNPs, 13, 13 and six protein coding genes were identified as potential candidates for PC1, PC2 and posterior lobe size, respectively. In addition to the previous findings showing that the intraspecific posterior shape variation are regulated by multiple QTL with strong effects, the present study suggests that the intraspecific variation may be under polygenic regulation with a number of loci with small effects. Further studies are required for investigating whether these candidate genes are responsible for the intraspecific posterior lobe shape variation.

  1. Genome-wide association study for cytokines and immunoglobulin G in swine.

    Xin Lu

    Full Text Available Increased disease resistance through improved immune capacity would be beneficial for the welfare and productivity of farm animals. To identify genomic regions responsible for immune capacity traits in swine, a genome-wide association study was conducted. In total, 675 pigs were included. At 21 days of age, all piglets were vaccinated with modified live classical swine fever vaccine. Blood samples were sampled when the piglets were 20 and 35 days of age, respectively. Four traits, including Interferon-gamma (IFN-γ and Interleukin 10 (IL-10 levels, the ratio of IFN-γ to IL-10 and Immunoglobulin G (IgG blocking percentage to CSFV in serum were measured. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP using the Illumina porcineSNP60k BeadChip. After quality control, 46,079 SNPs were selected for association tests based on a single-locus regression model. To tackle the issue of multiple testing, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance level. In total, 32 SNPs with chromosome-wise significance level (including 4 SNPs with genome-wise significance level were identified. These SNPs account for 3.23% to 13.81% of the total phenotypic variance individually. For the four traits, the numbers of significant SNPs range from 5 to 15, which jointly account for 37.52%, 82.94%, 26.74% and 24.16% of the total phenotypic variance of IFN-γ, IL-10, IFN-γ/IL-10, and IgG, respectively. Several significant SNPs are located within the QTL regions reported in previous studies. Furthermore, several significant SNPs fall into the regions which harbour a number of known immunity-related genes. Results herein lay a preliminary foundation for further identifying the causal mutations affecting swine immune capacity in follow-up studies.

  2. Patterns of Genome-Wide Variation in Glossina fuscipes fuscipes Tsetse Flies from Uganda.

    Gloria-Soria, Andrea; Dunn, W Augustine; Telleria, Erich L; Evans, Benjamin R; Okedi, Loyce; Echodu, Richard; Warren, Wesley C; Montague, Michael J; Aksoy, Serap; Caccone, Adalgisa

    2016-01-01

    The tsetse fly Glossina fuscipes fuscipes (Gff) is the insect vector of the two forms of Human African Trypanosomiasis (HAT) that exist in Uganda. Understanding Gff population dynamics, and the underlying genetics of epidemiologically relevant phenotypes is key to reducing disease transmission. Using ddRAD sequence technology, complemented with whole-genome sequencing, we developed a panel of ∼73,000 single-nucleotide polymorphisms (SNPs) distributed across the Gff genome that can be used for population genomics and to perform genome-wide-association studies. We used these markers to estimate genomic patterns of linkage disequilibrium (LD) in Gff, and used the information, in combination with outlier-locus detection tests, to identify candidate regions of the genome under selection. LD in individual populations decays to half of its maximum value (r(2) max/2) between 1359 and 2429 bp. The overall LD estimated for the species reaches r(2) max/2 at 708 bp, an order of magnitude slower than in Drosophila Using 53 infected (Trypanosoma spp.) and uninfected flies from four genetically distinct Ugandan populations adapted to different environmental conditions, we were able to identify SNPs associated with the infection status of the fly and local environmental adaptation. The extent of LD in Gff likely facilitated the detection of loci under selection, despite the small sample size. Furthermore, it is probable that LD in the regions identified is much higher than the average genomic LD due to strong selection. Our results show that even modest sample sizes can reveal significant genetic associations in this species, which has implications for future studies given the difficulties of collecting field specimens with contrasting phenotypes for association analysis. PMID:27172181

  3. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

    Rico Rueedi

    2014-02-01

    Full Text Available Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8 and independent associations between single nucleotide polymorphisms (SNP and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44 and lysine (rs8101881, P = 1.2×10(-33, respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

  4. Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers

    Litonjua Augusto A

    2011-06-01

    Full Text Available Abstract Background Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs, while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics. Methods In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS SNPs ranked by Random Forests (RF importance score for the CAMP (Childhood Asthma Management Program population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group. Results Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC = 0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors. Conclusions Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.

  5. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  6. Genome-wide association study of parity in Bangladeshi women.

    Aschebrook-Kilfoy, Briseis; Argos, Maria; Pierce, Brandon L; Tong, Lin; Jasmine, Farzana; Roy, Shantanu; Parvez, Faruque; Ahmed, Alauddin; Islam, Tariqul; Kibriya, Muhammad G; Ahsan, Habibul

    2015-01-01

    Human fertility is a complex trait determined by gene-environment interactions in which genetic factors represent a significant component. To better understand inter-individual variability in fertility, we performed one of the first genome-wide association studies (GWAS) of common fertility phenotypes, lifetime number of pregnancies and number of children in a developing country population. The fertility phenotype data and DNA samples were obtained at baseline recruitment from individuals participating in a large prospective cohort study in Bangladesh. GWAS analyses of fertility phenotypes were conducted among 1,686 married women. One SNP on chromosome 4 was non-significantly associated with number of children at P pregnancies at P pregnancies. This SNP is located near C5orf64, an open reading frame, and ZSWIM6, a zinc ion binding gene. We also estimated the heritability of these phenotypes from our genotype data using GCTA (Genome-wide Complex Trait Analysis) for number of children (hg2 = 0.149, SE = 0.24, p-value = 0.265) and number of pregnancies (hg2 = 0.007, SE = 0.22, p-value = 0.487). Our genome-wide association study and heritability estimates of number of pregnancies and number of children in Bangladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of 3 notable SNPs in their analysis. PMID:25742292

  7. Additive and epistatic genome-wide association for growth and ultrasound scan measures of carcass-related traits in Brahman cattle.

    Ali, A A; Khatkar, M S; Kadarmideen, H N; Thomson, P C

    2015-04-01

    Genome-wide association studies are routinely used to identify genomic regions associated with traits of interest. However, this ignores an important class of genomic associations, that of epistatic interactions. A genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) using highly dense markers can detect epistatic interactions, but is a difficult task due to multiple testing and computational demand. However, It is important for revealing complex trait heredity. This study considers analytical methods that detect statistical interactions between pairs of loci. We investigated a three-stage modelling procedure: (i) a model without the SNP to estimate the variance components; (ii) a model with the SNP using variance component estimates from (i), thus avoiding iteration; and (iii) using the significant SNPs from (ii) for genome-wide epistasis analysis. We fitted these three-stage models to field data for growth and ultrasound measures for subcutaneous fat thickness in Brahman cattle. The study demonstrated the usefulness of modelling epistasis in the analysis of complex traits as it revealed extra sources of genetic variation and identified potential candidate genes affecting the concentration of insulin-like growth factor-1 and ultrasound scan measure of fat depth traits. Information about epistasis can add to our understanding of the complex genetic networks that form the fundamental basis of biological systems. PMID:25754883

  8. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

    de Moor, Marleen H.M.; van den Berg, Stéphanie M.; Verweij, Karin J.H.; Krueger, Robert F.; Luciano, Michelle; Vasquez, Alejandro Arias; Matteson, Lindsay K.; Derringer, Jaime; Esko, Tõnu; Amin, Najaf; Gordon, Scott D.; Hansell, Narelle K.; Hart, Amy B.; Seppälä, Ilkka; Huffman, Jennifer E.; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Goncalo R.; Adkins, Daniel E.; Agrawal, Arpana; Allik, Jüri; Appel, Katja; Bigdeli, Timothy B.; Busonero, Fabio; Campbell, Harry; Costa, Paul T.; Smith, George Davey; Davies, Gail; de Wit, Harriet; Ding, Jun; Engelhardt, Barbara E.; Eriksson, Johan G.; Fedko, Iryna O.; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard; Hartmann, Annette M.; Heath, Andrew C.; Heinonen, Kati; Henders, Anjali K.; Homuth, Georg; Hottenga, Jouke-Jan; Janzing, Joost; Jokela, Markus; Karlsson, Robert; Kemp, John P.; Kirkpatrick, Matthew G.; Latvala, Antti; Lehtimäki, Terho; Liewald, David C.; Madden, Pamela A.F.; Magri, Chiara; Magnusson, Patrik K.E.; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E.; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W.; Nauck, Matthias; Ouwens, Klaasjan G.; Palotie, Aarno; Pettersson, Erik; Polasek, Ozren; Qian, Yong; Pulkki-Råback, Laura; Raitakari, Olli T.; Realo, Anu; Rose, Richard J.; Ruggiero, Daniela; Schmidt, Carsten O.; Slutske, Wendy S.; Sorice, Rossella; Starr, John M.; Pourcain, Beate St; Sutin, Angelina R.; Timpson, Nicholas J.; Trochet, Holly; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Wouda, Jasper; Wright, Margaret J.; Zgaga, Lina; Scotland, Generation; Porteous, David; Minelli, Alessandra; Palmer, Abraham A.; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J.; Räikkönen, Katri; Wilson, James F.; Keltikangas-Järvinen, Liisa; Bierut, Laura J.; Hettema, John M.; Grabe, Hans J.; van Duijn, Cornelia M.; Evans, David M.; Schlessinger, David; Pedersen, Nancy L.; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W.J.H.; Martin, Nicholas G.; Boomsma, Dorret I.

    2015-01-01

    Importance Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases). Objective To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD. Setting 30 cohorts with genome-wide genotype, personality and MDD data from the GPC. Participants The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia. Main outcome measure(s) Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status. Results A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts. Conclusions and relevance This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study

  9. A genome-wide association study in chronic obstructive pulmonary disease (COPD: identification of two major susceptibility loci.

    Sreekumar G Pillai

    2009-03-01

    Full Text Available There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD. The only known genetic risk factor is severe deficiency of alpha(1-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls and evaluated the top 100 single nucleotide polymorphisms (SNPs in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT and 472 controls from the Normative Aging Study (NAS and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5 locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10, (rs8034191 and 5.74 x 10(-10 (rs1051730. Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article

  10. Pathway-based analysis using genome-wide association data from a Korean non-small cell lung cancer study.

    Donghoon Lee

    Full Text Available Pathway-based analysis, used in conjunction with genome-wide association study (GWAS techniques, is a powerful tool to detect subtle but systematic patterns in genome that can help elucidate complex diseases, like cancers. Here, we stepped back from genetic polymorphisms at a single locus and examined how multiple association signals can be orchestrated to find pathways related to lung cancer susceptibility. We used single-nucleotide polymorphism (SNP array data from 869 non-small cell lung cancer (NSCLC cases from a previous GWAS at the National Cancer Center and 1,533 controls from the Korean Association Resource project for the pathway-based analysis. After mapping single-nucleotide polymorphisms to genes, considering their coding region and regulatory elements (±20 kbp, multivariate logistic regression of additive and dominant genetic models were fitted against disease status, with adjustments for age, gender, and smoking status. Pathway statistics were evaluated using Gene Set Enrichment Analysis (GSEA and Adaptive Rank Truncated Product (ARTP methods. Among 880 pathways, 11 showed relatively significant statistics compared to our positive controls (PGSEA≤0.025, false discovery rate≤0.25. Candidate pathways were validated using the ARTP method and similarities between pathways were computed against each other. The top-ranked pathways were ABC Transporters (PGSEA<0.001, PARTP = 0.001, VEGF Signaling Pathway (PGSEA<0.001, PARTP = 0.008, G1/S Check Point (PGSEA = 0.004, PARTP = 0.013, and NRAGE Signals Death through JNK (PGSEA = 0.006, PARTP = 0.001. Our results demonstrate that pathway analysis can shed light on post-GWAS research and help identify potential targets for cancer susceptibility.

  11. A comparative genomics strategy for targeted discovery of single-nucleotide polymorphisms and conserved-noncoding sequences in orphan crops.

    Feltus, F A; Singh, H P; Lohithaswa, H C; Schulze, S R; Silva, T D; Paterson, A H

    2006-04-01

    Completed genome sequences provide templates for the design of genome analysis tools in orphan species lacking sequence information. To demonstrate this principle, we designed 384 PCR primer pairs to conserved exonic regions flanking introns, using Sorghum/Pennisetum expressed sequence tag alignments to the Oryza genome. Conserved-intron scanning primers (CISPs) amplified single-copy loci at 37% to 80% success rates in taxa that sample much of the approximately 50-million years of Poaceae divergence. While the conserved nature of exons fostered cross-taxon amplification, the lesser evolutionary constraints on introns enhanced single-nucleotide polymorphism detection. For example, in eight rice (Oryza sativa) genotypes, polymorphism averaged 12.1 per kb in introns but only 3.6 per kb in exons. Curiously, among 124 CISPs evaluated across Oryza, Sorghum, Pennisetum, Cynodon, Eragrostis, Zea, Triticum, and Hordeum, 23 (18.5%) seemed to be subject to rigid intron size constraints that were independent of per-nucleotide DNA sequence variation. Furthermore, we identified 487 conserved-noncoding sequence motifs in 129 CISP loci. A large CISP set (6,062 primer pairs, amplifying introns from 1,676 genes) designed using an automated pipeline showed generally higher abundance in recombinogenic than in nonrecombinogenic regions of the rice genome, thus providing relatively even distribution along genetic maps. CISPs are an effective means to explore poorly characterized genomes for both DNA polymorphism and noncoding sequence conservation on a genome-wide or candidate gene basis, and also provide anchor points for comparative genomics across a diverse range of species. PMID:16607031

  12. A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs).

    Brütting, Christine; Emmer, Alexander; Kornhuber, Malte; Staege, Martin S

    2016-08-01

    Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far. PMID:27169423

  13. Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms

    Majewski Jacek

    2006-08-01

    Full Text Available Abstract Background Complementary single-nucleotide polymorphisms (SNPs may not be distributed equally between two DNA strands if the strands are functionally distinct, such as in transcribed genes. In introns, an excess of A↔G over the complementary C↔T substitutions had previously been found and attributed to transcription-coupled repair (TCR, demonstrating the valuable functional clues that can be obtained by studying such asymmetry. Here we studied asymmetry of human synonymous SNPs (sSNPs in the fourfold degenerate (FFD sites as compared to intronic SNPs (iSNPs. Results The identities of the ancestral bases and the direction of mutations were inferred from human-chimpanzee genomic alignment. After correction for background nucleotide composition, excess of A→G over the complementary T→C polymorphisms, which was observed previously and can be explained by TCR, was confirmed in FFD SNPs and iSNPs. However, when SNPs were separately examined according to whether they mapped to a CpG dinucleotide or not, an excess of C→T over G→A polymorphisms was found in non-CpG site FFD SNPs but was absent from iSNPs and CpG site FFD SNPs. Conclusion The genome-wide discrepancy of human FFD SNPs provides novel evidence for widespread selective pressure due to functional effects of sSNPs. The similar asymmetry pattern of FFD SNPs and iSNPs that map to a CpG can be explained by transcription-coupled mechanisms, including TCR and transcription-coupled mutation. Because of the hypermutability of CpG sites, more CpG site FFD SNPs are relatively younger and have confronted less selection effect than non-CpG FFD SNPs, which can explain the asymmetric discrepancy of CpG site FFD SNPs vs. non-CpG site FFD SNPs.

  14. Impact of Il28b-related single nucleotide polymorphisms on liver transient elastography in chronic hepatitis C infection.

    Magdalena Ydreborg

    Full Text Available BACKGROUND AND AIMS: Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs in proximity to IL28B predict spontaneous clearance of hepatitis C virus (HCV infection as well as outcome following pegylated interferon and ribavirin therapy among genotype 1 infected patients. Additionally the presence of the otherwise favorable IL28B genetic variants in the context of HCV genotype 3 infection reportedly entail more pronounced liver fibrosis and steatosis. The present study aimed to evaluate the impact of IL28B SNP variability on liver stiffness as accessed by transient elastography. METHODS: Seven hundred and seventy-one Swedish HCV infected patients sequentially undergoing liver stiffness measurement by means of Fibroscan® in the context of a real-life trial had samples available for IL28B genotyping (rs12979860 and HCV genotyping. RESULTS: CC(rs12979860 was more common among HCV genotype 2 or 3 infected treatment-naïve patients than among those infected with genotype 1 (P<0.0001. Additionally CC(rs12979860 among HCV genotype 3 infected patients was associated with higher liver stiffness values (P = 0.004, and higher AST to platelet ratio index (APRI; p = 0.02 as compared to carriers of the T allele. Among HCV genotype 1 infected patients, CC(rs12979860 was significantly associated with higher viral load (P = 0.001, with a similar non-significant trend noted among HCV genotype 3 infected patients. CONCLUSION: This study confirms previous reports that the CC(rs12979860 SNP is associated with more pronounced liver pathology in patients chronically infected with HCV genotype 3 as compared to genotype 1, suggesting that IL28B genetic variants differently regulates the course of HCV infection across HCV genotypes.

  15. Optimization of Bartonella henselae multilocus sequence typing scheme using single-nucleotide polymorphism analysis of SOLiD sequence data

    ZHAO Fan; Gemma Chaloner; Alistair Darby; SONG Xiu-ping; LI Dong-mei; Richard Birtles; LIU Qi-yong

    2012-01-01

    Background Multi-locus sequence typing (MLST) is widely used to explore the population structure of numerous bacterial pathogens.However,for genotypically-restricted pathogens,the sensitivity of MLST is limited by a paucity of variation within selected loci.For Bartonella henselae (B.henselae),although the MLST scheme currently used has been proven useful in defining the overall population structure of the species,its reliability for the accurate delineation of closely-related sequence types,between which allelic variation is usually limited to,at most,one or two nucleotide polymorphisms.Exploitation of high-throughput sequencing data allows a more informed selection of MLST loci and thus,potentially,a means of enhancing the sensitivity of the schemes they comprise.Methods We carried out SOLiD resequencing on 12 representative B.henselae isolates and explored these data using single nucleotide polymorphism (SNP) analysis.We determined the number and distribution of SNPs in the genes targeted by the established MLST scheme and modified the position of loci within these genes to capture as much genetic variation as possible.Results Using genome-wide SNP data,we found the distribution of SNPs within each open reading frame (ORF) of MLST loci,which were not represented by the established B.henselae MLST scheme.We then modified the position of loci in the MLST scheme to better reflect the polymorphism in the ORF as a whole.The use of amended loci in this scheme allowed previously indistinguishable ST1 strains to be differentiated.However,the diversity of B.henselae was still rare in China.Conclusions Our study demonstrates the use of SNP analysis to facilitate the selection of MLST loci to augment the currently-described scheme for B.henselae.And the diversity among B.henselae strains in China is markedly less than that observed in B.henselae populations elsewhere in the world.

  16. Genome-wide linkage analysis for human longevity

    Beekman, Marian; Blanché, Hélène; Perola, Markus;

    2013-01-01

    Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian...... sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2...

  17. [New insight of genome-wide association study (GWAS)].

    Hotta, Kikuko

    2013-02-01

    The number of obese patients is increasing in Japan, due to the westernization of lifestyle. Obesity, especially visceral fat obesity, is important for the development of metabolic syndrome. Genetic factors are important for the development of obesity as well as environmental factors. Importance of genetic factors of fat distribution is also reported. Recent genome-wide association studies (GWASs) have revealed the obesity and fat distribution-related polymorphisms. GWAS will highlight a better understanding of the underlying molecular mechanisms in the regulation of obesity and distribution of body fat. PMID:23631198

  18. [Genome-wide association study for adolescent idiopathic scoliosis].

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS. PMID:27013625

  19. Genome-wide mapping of DNA strand breaks.

    Frédéric Leduc

    Full Text Available Determination of cellular DNA damage has so far been limited to global assessment of genome integrity whereas nucleotide-level mapping has been restricted to specific loci by the use of specific primers. Therefore, only limited DNA sequences can be studied and novel regions of genomic instability can hardly be discovered. Using a well-characterized yeast model, we describe a straightforward strategy to map genome-wide DNA strand breaks without compromising nucleotide-level resolution. This technique, termed "damaged DNA immunoprecipitation" (dDIP, uses immunoprecipitation and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL to capture DNA at break sites. When used in combination with microarray or next-generation sequencing technologies, dDIP will allow researchers to map genome-wide DNA strand breaks as well as other types of DNA damage and to establish a clear profiling of altered genes and/or intergenic sequences in various experimental conditions. This mapping technique could find several applications for instance in the study of aging, genotoxic drug screening, cancer, meiosis, radiation and oxidative DNA damage.

  20. Genome-wide identification of hypoxia-induced enhancer regions

    Preston, Jessica L.; Randel, Melissa A.; Johnson, Eric A.

    2015-01-01

    Here we present a genome-wide method for de novo identification of enhancer regions. This approach enables massively parallel empirical investigation of DNA sequences that mediate transcriptional activation and provides a platform for discovery of regulatory modules capable of driving context-specific gene expression. The method links fragmented genomic DNA to the transcription of randomer molecule identifiers and measures the functional enhancer activity of the library by massively parallel sequencing. We transfected a Drosophila melanogaster library into S2 cells in normoxia and hypoxia, and assayed 4,599,881 genomic DNA fragments in parallel. The locations of the enhancer regions strongly correlate with genes up-regulated after hypoxia and previously described enhancers. Novel enhancer regions were identified and integrated with RNAseq data and transcription factor motifs to describe the hypoxic response on a genome-wide basis as a complex regulatory network involving multiple stress-response pathways. This work provides a novel method for high-throughput assay of enhancer activity and the genome-scale identification of 31 hypoxia-activated enhancers in Drosophila. PMID:26713262

  1. Genome-wide association study of periodontal pathogen colonization.

    Divaris, K; Monda, K L; North, K E; Olshan, A F; Lange, E M; Moss, K; Barros, S P; Beck, J D; Offenbacher, S

    2012-07-01

    Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom "checkerboard" DNA-DNA hybridization quantification of 8 periodontal pathogens was performed. We examined 3 traits: "high red" and "high orange" bacterial complexes, and "high" Aggregatibacter actinomycetemcomitans (Aa) colonization. Genotyping was performed on the Affymetrix 6.0 platform. Imputation to 2.5 million markers was based on HapMap II-CEU, and a multiple-test correction was applied (genome-wide threshold of p orange" complex microbiota, but not for Aa, had the same effect direction in a second sample of 123 African-American participants. None of these polymorphisms was associated with periodontitis diagnosis. Investigations replicating these findings may lead to an improved understanding of the complex nature of host-microbiome interactions that characterizes states of health and disease. PMID:22699663

  2. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Varun Warrier

    Full Text Available Asperger Syndrome (AS is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC, which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448 were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448 lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  3. Establishing an analytic pipeline for genome-wide DNA methylation.

    Wright, Michelle L; Dozmorov, Mikhail G; Wolen, Aaron R; Jackson-Cook, Colleen; Starkweather, Angela R; Lyon, Debra E; York, Timothy P

    2016-01-01

    The need for research investigating DNA methylation (DNAm) in clinical studies has increased, leading to the evolution of new analytic methods to improve accuracy and reproducibility of the interpretation of results from these studies. The purpose of this article is to provide clinical researchers with a summary of the major data processing steps routinely applied in clinical studies investigating genome-wide DNAm using the Illumina HumanMethylation 450K BeadChip. In most studies, the primary goal of employing DNAm analysis is to identify differential methylation at CpG sites among phenotypic groups. Experimental design considerations are crucial at the onset to minimize bias from factors related to sample processing and avoid confounding experimental variables with non-biological batch effects. Although there are currently no de facto standard methods for analyzing these data, we review the major steps in processing DNAm data recommended by several research studies. We describe several variations available for clinical researchers to process, analyze, and interpret DNAm data. These insights are applicable to most types of genome-wide DNAm array platforms and will be applicable for the next generation of DNAm array technologies (e.g., the 850K array). Selection of the DNAm analytic pipeline followed by investigators should be guided by the research question and supported by recently published methods. PMID:27127542

  4. Genome-wide analysis of DNA methylation in hepatoblastoma tissues

    Cui, Ximao; Liu, Baihui; Zheng, Shan; Dong, Kuiran; Dong, Rui

    2016-01-01

    DNA methylation has a crucial role in cancer biology. In the present study, a genome-wide analysis of DNA methylation in hepatoblastoma (HB) tissues was performed to verify differential methylation levels between HB and normal tissues. As alpha-fetoprotein (AFP) has a critical role in HB, AFP methylation levels were also detected using pyrosequencing. Normal and HB liver tissue samples (frozen tissue) were obtained from patients with HB. Genome-wide analysis of DNA methylation in these tissues was performed using an Infinium HumanMethylation450 BeadChip, and the results were confirmed with reverse transcription-quantitative polymerase chain reaction. The Infinium HumanMethylation450 BeadChip demonstrated distinctively less methylation in HB tissues than in non-tumor tissues. In addition, methylation enrichment was observed in positions near the transcription start site of AFP, which exhibited lower methylation levels in HB tissues than in non-tumor liver tissues. Lastly, a significant negative correlation was observed between AFP messenger RNA expression and DNA methylation percentage, using linear Pearson's R correlation coefficients. The present results demonstrate differential methylation levels between HB and normal tissues, and imply that aberrant methylation of AFP in HB could reflect HB development. Expansion of these findings could provide useful insight into HB biology.

  5. Genome-Wide Scan for Methylation Profiles in Keloids

    Lamont R. Jones

    2015-01-01

    Full Text Available Keloids are benign fibroproliferative tumors of the skin which commonly occur after injury mainly in darker skinned patients. Medical treatment is fraught with high recurrence rates mainly because of an incomplete understanding of the biological mechanisms that lead to keloids. The purpose of this project was to examine keloid pathogenesis from the epigenome perspective of DNA methylation. Genome-wide profiling used the Infinium HumanMethylation450 BeadChip to interrogate DNA from 6 fresh keloid and 6 normal skin samples from 12 anonymous donors. A 3-tiered approach was used to call out genes most differentially methylated between keloid and normal. When compared to normal, of the 685 differentially methylated CpGs at Tier 3, 510 were hypomethylated and 175 were hypermethylated with 190 CpGs in promoter and 495 in nonpromoter regions. The 190 promoter region CpGs corresponded to 152 genes: 96 (63% were hypomethylated and 56 (37% hypermethylated. This exploratory genome-wide scan of the keloid methylome highlights a predominance of hypomethylated genomic landscapes, favoring nonpromoter regions. DNA methylation, as an additional mechanism for gene regulation in keloid pathogenesis, holds potential for novel treatments that reverse deleterious epigenetic changes. As an alternative mechanism for regulating genes, epigenetics may explain why gene mutations alone do not provide definitive mechanisms for keloid formation.

  6. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette Syndrome and Obsessive-Compulsive Disorder

    Yu, Dongmei; Mathews, Carol A.; Scharf, Jeremiah M.; Neale, Benjamin M.; Davis, Lea K.; Gamazon, Eric R.; Derks, Eske M.; Evans, Patrick; Edlund, Christopher K.; Crane, Jacquelyn; Fagerness, Jesen A.; Osiecki, Lisa; Gallagher, Patience; Gerber, Gloria; Haddad, Stephen; Illmann, Cornelia; McGrath, Lauren M.; Mayerfeld, Catherine; Arepalli, Sampath; Barlassina, Cristina; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrió, Gabriel Bedoya; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Brentani, Helena; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond D.; Cappi, Carolina; Cardona Silgado, Julio C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Cook, Edwin H.; Cookson, M. R.; Coric, Vladimir; Cullen, Bernadette; Cusi, Daniele; Delorme, Richard; Denys, Damiaan; Dion, Yves; Eapen, Valsama; Egberts, Karin; Falkai, Peter; Fernandez, Thomas; Fournier, Eduardo; Garrido, Helena; Geller, Daniel; Gilbert, Donald; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Grünblatt, Edna; Hardy, John; Heiman, Gary A.; Hemmings, Sian M.J.; Herrera, Luis D.; Hezel, Dianne M.; Hoekstra, Pieter J.; Jankovic, Joseph; Kennedy, James L.; King, Robert A.; Konkashbaev, Anuar I.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Lupoli, Sara; Macciardi, Fabio; Maier, Wolfgang; Manunta, Paolo; Marconi, Maurizio; McCracken, James T.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Moorjani, Priya; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosário, Maria C.; Rosenberg, David; Ruhrmann, Stephan; Sabatti, Chiara; Salvi, Erika; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Service, Susan K.; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, Eric; Tischfield, Jay A.; Turiel, Maurizio; Valencia Duarte, Ana V.; Vallada, Homero; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Walkup, John; Wang, Ying; Weale, Mike; Weiss, Robert; Wendland, Jens R.; Westenberg, Herman G.M.; Yao, Yin; Hounie, Ana G.; Miguel, Euripedes C.; Nicolini, Humberto; Wagner, Michael; Ruiz-Linares, Andres; Cath, Danielle C.; McMahon, William; Posthuma, Danielle; Oostra, Ben A.; Nestadt, Gerald; Rouleau, Guy A.; Purcell, Shaun; Jenike, Michael A.; Heutink, Peter; Hanna, Gregory L.; Conti, David V.; Arnold, Paul D.; Freimer, Nelson; Stewart, S. Evelyn; Knowles, James A.; Cox, Nancy J.; Pauls, David L.

    2014-01-01

    Obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. Here, we report a combined genome-wide association study (GWAS) of TS and OCD in 2723 cases (1310 with OCD, 834 with TS, 579 with OCD plus TS/chronic tics (CT)), 5667 ancestry-matched controls, and 290 OCD parent-child trios. Although no individual single nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels, i.e. expression quantitative loci (eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, TS had a smaller, non-significant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and TS/CT were included in the analysis (p=0.01). Previous work has shown that TS and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of TS and OCD. Furthermore, OCD with co-occurring TS/CT may have different underlying genetic susceptibility compared to OCD alone. PMID:25158072

  7. A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants.

    Vaysse, Amaury; Fang, Shenying; Brossard, Myriam; Wei, Qingyi; Chen, Wei V; Mohamdi, Hamida; Vincent-Fetita, Lynda; Margaritte-Jeannin, Patricia; Lavielle, Nolwenn; Maubec, Eve; Lathrop, Mark; Avril, Marie-Françoise; Amos, Christopher I; Lee, Jeffrey E; Demenais, Florence

    2016-11-01

    Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (pmeta-int =2.2 × 10(-6) , which met the overall multiple-testing corrected threshold of 2.5 × 10(-6) ). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion. PMID:27347659

  8. Heritability and genome-wide association analysis of renal sinus fat accumulation in the Framingham Heart Study

    Foster Meredith C

    2011-11-01

    Full Text Available Abstract Background Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized. Methods The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1 age, (2 age and body mass index (BMI, and (3 age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs. Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n = 16, BMI (n = 32, and waist-to-hip ratio (WHR, n = 14, and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat. Results The heritability of renal sinus fat was 39% (p Conclusions Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.

  9. Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151).

    Davies, G; Marioni, R E; Liewald, D C; Hill, W D; Hagenaars, S P; Harris, S E; Ritchie, S J; Luciano, M; Fawns-Ritchie, C; Lyall, D; Cullen, B; Cox, S R; Hayward, C; Porteous, D J; Evans, J; McIntosh, A M; Gallacher, J; Craddock, N; Pell, J P; Smith, D J; Gale, C R; Deary, I J

    2016-06-01

    People's differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal-numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal-numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer's disease and schizophrenia. PMID:27046643

  10. Genome-wide association study of autistic-like traits in a general population study of young adults

    Rachel Maree Jones

    2013-10-01

    Full Text Available Research has proposed that autistic-like traits in the general population lie on a continuum, with clinical Autism Spectrum Disorder (ASD representing the extreme end of this distribution. Inherent in this proposal is that biological mechanisms associated with clinical ASD may also underpin variation in autistic-like traits within the general population. A genome-wide association study using 2,462,046 single nucleotide polymorphisms (SNPs was undertaken for ASD in 965 individuals from the Western Australian Pregnancy Cohort (Raine Study. No SNP associations reached genome-wide significance (p < 5.0 x 10-8. However, investigations into nominal observed SNP associations (p < 1.0 x 10-5 add support to two positional candidate genes previously implicated in ASD aetiology, PRKCB1 and CBLN1.The rs198198 SNP (p = 9.587 x 10-6, is located within an intron of the protein kinase C, beta 1 (PRKCB1 gene on chromosome 16p11. The PRKCB1 gene has been previously reported in linkage and association studies for ASD, and its mRNA expression has been shown to be significantly down regulated in ASD cases compared with controls. The rs16946931 SNP (p = 1.78 x 10-6 is located in a region flanking the Cerebellin 1 (CBLN1 gene on chromosome 16q12.1. The CBLN1 gene is involved with synaptogenesis and is part of a gene family previously implicated in ASD. This GWA study is only the second to examine SNPs associated with autistic-like traits in the general population, and provides evidence to support roles for the PRKCB1 and CBLN1 genes in risk of clinical ASD.

  11. Genome-wide association analysis for quantitative trait loci influencing Warner–Bratzler shear force in five taurine cattle breeds

    McClure, M C; Ramey, H R; Rolf, M M; McKay, S D; Decker, J E; Chapple, R H; Kim, J W; Taxis, T M; Weaber, R L; Schnabel, R D; Taylor, J F

    2012-01-01

    Summary We performed a genome-wide association study for Warner–Bratzler shear force (WBSF), a measure of meat tenderness, by genotyping 3360 animals from five breeds with 54 790 BovineSNP50 and 96 putative single-nucleotide polymorphisms (SNPs) within μ-calpain [HUGO nomenclature calpain 1, (mu/I) large subunit; CAPN1] and calpastatin (CAST). Within- and across-breed analyses estimated SNP allele substitution effects (ASEs) by genomic best linear unbiased prediction (GBLUP) and variance components by restricted maximum likelihood under an animal model incorporating a genomic relationship matrix. GBLUP estimates of ASEs from the across-breed analysis were moderately correlated (0.31–0.66) with those from the individual within-breed analyses, indicating that prediction equations for molecular estimates of breeding value developed from across-breed analyses should be effective for genomic selection within breeds. We identified 79 genomic regions associated with WBSF in at least three breeds, but only eight were detected in all five breeds, suggesting that the within-breed analyses were underpowered, that different quantitative trait loci (QTL) underlie variation between breeds or that the BovineSNP50 SNP density is insufficient to detect common QTL among breeds. In the across-breed analysis, CAPN1 was followed by CAST as the most strongly associated WBSF QTL genome-wide, and associations with both were detected in all five breeds. We show that none of the four commercialized CAST and CAPN1SNP diagnostics are causal for associations with WBSF, and we putatively fine-map the CAPN1 causal mutation to a 4581-bp region. We estimate that variation in CAST and CAPN1 explains 1.02 and 1.85% of the phenotypic variation in WBSF respectively. PMID:22497286

  12. Genome-wide association study of young-onset hypertension in the Han Chinese population of Taiwan.

    Hsin-Chou Yang

    Full Text Available Young-onset hypertension has a stronger genetic component than late-onset counterpart; thus, the identification of genes related to its susceptibility is a critical issue for the prevention and management of this disease. We carried out a two-stage association scan to map young-onset hypertension susceptibility genes. The first-stage analysis, a genome-wide association study, analyzed 175 matched case-control pairs; the second-stage analysis, a confirmatory association study, verified the results at the first stage based on a total of 1,008 patients and 1,008 controls. Single-locus association tests, multilocus association tests and pair-wise gene-gene interaction tests were performed to identify young-onset hypertension susceptibility genes. After considering stringent adjustments of multiple testing, gene annotation and single-nucleotide polymorphism (SNP quality, four SNPs from two SNP triplets with strong association signals (-log(10(p>7 and 13 SNPs from 8 interactive SNP pairs with strong interactive signals (-log(10(p>8 were carefully re-examined. The confirmatory study verified the association for a SNP quartet 219 kb and 495 kb downstream of LOC344371 (a hypothetical gene and RASGRP3 on chromosome 2p22.3, respectively. The latter has been implicated in the abnormal vascular responsiveness to endothelin-1 and angiotensin II in diabetic-hypertensive rats. Intrinsic synergy involving IMPG1 on chromosome 6q14.2-q15 was also verified. IMPG1 encodes interphotoreceptor matrix proteoglycan 1 which has cation binding capacity. The genes are novel hypertension targets identified in this first genome-wide hypertension association study of the Han Chinese population.

  13. Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

    Song, J; Bergen, S E; Di Florio, A; Karlsson, R; Charney, A; Ruderfer, D M; Stahl, E A; Chambert, K D; Moran, J L; Gordon-Smith, K; Forty, L; Green, E K; Jones, I; Jones, L; Scolnick, E M; Sklar, P; Smoller, J W; Lichtenstein, P; Hultman, C; Craddock, N; Landén, M; Smoller, Jordan W; Perlis, Roy H; Lee, Phil Hyoun; Castro, Victor M; Hoffnagle, Alison G; Sklar, Pamela; Stahl, Eli A; Purcell, Shaun M; Ruderfer, Douglas M; Charney, Alexander W; Roussos, Panos; Michele Pato, Carlos Pato; Medeiros, Helen; Sobel, Janet; Craddock, Nick; Jones, Ian; Forty, Liz; Florio, Arianna Di; Green, Elaine; Jones, Lisa; Gordon-Smith, Katherine; Landen, Mikael; Hultman, Christina; Jureus, Anders; Bergen, Sarah; McCarroll, Steven; Moran, Jennifer; Smoller, Jordan W; Chambert, Kimberly; Belliveau, Richard A

    2016-09-01

    Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD. PMID:26503763

  14. Cost-effective genome-wide estimation of allele frequencies from pooled DNA in Atlantic salmon (Salmo salar L.

    Ozerov Mikhail

    2013-01-01

    Full Text Available Abstract Background New sequencing technologies have tremendously increased the number of known molecular markers (single nucleotide polymorphisms; SNPs in a variety of species. Concurrently, improvements to genotyping technology have now made it possible to efficiently genotype large numbers of genome-wide distributed SNPs enabling genome wide association studies (GWAS. However, genotyping significant numbers of individuals with large number of SNPs remains prohibitively expensive for many research groups. A possible solution to this problem is to determine allele frequencies from pooled DNA samples, such ‘allelotyping’ has been presented as a cost-effective alternative to individual genotyping and has become popular in human GWAS. In this article we have tested the effectiveness of DNA pooling to obtain accurate allele frequency estimates for Atlantic salmon (Salmo salar L. populations using an Illumina SNP-chip. Results In total, 56 Atlantic salmon DNA pools from 14 populations were analyzed on an Atlantic salmon SNP-chip containing probes for 5568 SNP markers, 3928 of which were bi-allelic. We developed an efficient quality control filter which enables exclusion of loci showing high error rate and minor allele frequency (MAF close to zero. After applying multiple quality control filters we obtained allele frequency estimates for 3631 bi-allelic loci. We observed high concordance (r > 0.99 between allele frequency estimates derived from individual genotyping and DNA pools. Our results also indicate that even relatively small DNA pools (35 individuals can provide accurate allele frequency estimates for a given sample. Conclusions Despite of higher level of variation associated with array replicates compared to pool construction, we suggest that both sources of variation should be taken into account. This study demonstrates that DNA pooling allows fast and high-throughput determination of allele frequencies in Atlantic salmon enabling cost

  15. Genome-wide association study identifies multiple novel loci associated with disease progression in subjects with mild cognitive impairment.

    Hu, X; Pickering, E H; Hall, S K; Naik, S; Liu, Y C; Soares, H; Katz, E; Paciga, S A; Liu, W; Aisen, P S; Bales, K R; Samad, T A; John, S L

    2011-01-01

    Alzheimer's disease (AD) is the leading cause of dementia among the elderly population; however, knowledge about genetic risk factors involved in disease progression is limited. We conducted a genome-wide association study (GWAS) using clinical decline as measured by changes in the Clinical Dementia Rating-sum of boxes as a quantitative trait to test for single-nucleotide polymorphisms (SNPs) that were associated with the rate of progression in 822 Caucasian subjects of amnestic mild cognitive impairment (MCI). There was no significant association with disease progress for any of the recently identified disease susceptibility variants in CLU, CR1, PICALM, BIN1, EPHA1, MS4A6A, MS4A4E or CD33 following multiple testing correction. We did, however, identify multiple novel loci that reached genome-wide significance at the 0.01 level. These top variants (rs7840202 at chr8 in UBR5: P=4.27 × 10(-14); rs11637611 with a cluster of SNPs at chr15q23 close to the Tay-Sachs disease locus: P=1.07 × 10(-15); and rs12752888 at chr1: P=3.08 × 10(-11)) were also associated with a significant decline in cognition as well as the conversion of subjects with MCI to a diagnosis of AD. Taken together, these variants define approximately 16.6% of the MCI sub-population with a faster rate of decline independent of the other known disease risk factors. In addition to providing new insights into protein pathways that may be involved with the progress to AD in MCI subjects, these variants if further validated may enable the identification of a more homogeneous population of subjects at an earlier stage of disease for testing novel hypotheses and/or therapies in the clinical setting. PMID:22833209

  16. Opportunities for genome-wide selection for pig breeding in developing countries.

    Akanno, E C; Schenkel, F S; Sargolzaei, M; Friendship, R M; Robinson, J A B

    2013-10-01

    Genetic improvement of exotic and indigenous pigs in tropical developing countries is desired. Implementations of traditional selection methods on tropical pig populations are limited by lack of data recording and analysis infrastructure. Genome-wide selection (GS) provides an approach for achieving faster genetic progress without developing a pedigree recording system. The implications of GS on long-term gain and inbreeding should be studied before actual implementation, especially where low linkage disequilibrium (LD) is anticipated in the target population. A simulation case study of this option was performed on the basis of the available 60,000 SNP panel for porcine genome. Computer simulation was used to explore the effects of various selection methods, trait heritability, and different breeding programs when applying GS. Genomic predictions were based on the ridge regression method. Genome-wide selection performed better than BLUP and phenotypic selection methods by increasing genetic gain and maintaining genetic variation while lowering inbreeding, especially for traits with low heritability. Indigenous pig populations with low LD can be improved by using GS if high-density marker panels are available. The combination of GS with repeated backcrossing of crossbreds to exotic pigs in developing countries promises to rapidly improve the genetic merit of the commercial population. Application of this novel method on a real population will need to be performed to validate these results. PMID:24078617

  17. Relationships among calpastatin single nucleotide polymorphisms, calpastatin expression and tenderness in pork longissimus

    Genome scans in the pig have identified a region on chromosome 2 (SSC2) associated with tenderness. Calpastatin is a likely positional candidate gene in this region because of its inhibitory role in the calpain system that is involved in postmortem tenderization. Novel single nucleotide polymorphism...

  18. Single nucleotide polymorphisms in sheep varying in tolerance to elevated dietary nitrate

    Discovery of single nucleotide polymorphisms (SNPs) may lead to development of marker panels predictive of tolerance to high dietary nitrate (NO3-). The aims of this research were to identify SNPs in Arginiosuccinate Lyase (ASL), determine the relationship of ASL SNP genotypes on NO3- tolerance, an...

  19. Targeted Metabolic Engineering Guided by Computational Analysis of Single-Nucleotide Polymorphisms (SNPs)

    Udatha, D B R K Gupta; Rasmussen, Simon; Sicheritz-Pontén, Thomas;

    2013-01-01

    The non-synonymous SNPs, the so-called non-silent SNPs, which are single-nucleotide variations in the coding regions that give "birth" to amino acid mutations, are often involved in the modulation of protein function. Understanding the effect of individual amino acid mutations on a protein...

  20. Short communication: Relationship of call rate and accuracy of single nucleotide polymorphism genotypes in dairy cattle

    Call rate has been used as a measure of quality on both a single nucleotide polymorphism (SNP) and animal basis since SNP genotypes were first used in genomic evaluation of dairy cattle. The genotyping laboratories perform initial quality control screening and genotypes that fail are usually exclude...

  1. Association of single nucleotide polymorphisms in candidate genes residing under quantitative trait loci in beef cattle

    The objective was to assess the association of single nucleotide polymorphisms (SNP) developed on candidate genes residing under previously identified quantitative trait loci for marbling score and meat tenderness. Two hundred five SNP were identified on twenty candidate genes. Genes selected under ...

  2. Development of a web services based system for dissemination of single nucleotide polymorphism data

    Single nucleotide polymorphisms (SNPs) can be used to generate DNA-based fingerprints for individual identification. The efficiency of DNA fingerprinting is greatest when the frequency of both SNP alleles is near 0.50. A number of SNPs have been identified in cattle populations with minor allele f...

  3. Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

    Kjær, Karina Hansen; Pahus, Jytte; Hansen, Mariann Fagernæs;

    2014-01-01

    cellular RNAs which in turn inhibits protein translation and induces apoptosis. Several single nucleotide polymorphisms (SNPs) in the OAS1 gene have been associated with disease. We have investigated the functional effect of two common SNPs in the OAS1 gene. The SNP rs10774671 affects splicing to one of...

  4. Twelve single nucleotide polymorphisms on chromosome 19q13.2-13.3

    Yin, Jiaoyang; Vogel, Ulla; Gerdes, Lars Ulrik;

    2003-01-01

    The genetic susceptibility to basal cell carcinoma (BCC) among Danish psoriatic patients was investigated in association studies with 12 single nucleotide polymorphisms on chromosome 19q13.2-3. The results show a significant association between BCC and the A-allele of a polymorphism in ERCCI exon4...

  5. Genome wide high density SNP-based linkage analysis of childhood absence epilepsy identifies a susceptibility locus on chromosome 3p23-p14

    Chioza, Barry A; Aicardi, Jean; Aschauer, Harald;

    2009-01-01

    and the genes involved are yet to be fully established. A genome wide single nucleotide polymorphism (SNP)-based high density linkage scan was carried out using 41 nuclear pedigrees with at least two affected members. Multipoint parametric and non-parametric linkage analyses were performed using...... MERLIN 1.1.1 and a susceptibility locus was identified on chromosome 3p23-p14 (Z(mean)=3.9, p<0.0001; HLOD=3.3, alpha=0.7). The linked region harbours the functional candidate genes TRAK1 and CACNA2D2. Fine-mapping using a tagSNP approach demonstrated disease association with variants in TRAK1....

  6. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs

    Schork, Andrew J; Thompson, Wesley K; Pham, Phillip;

    2013-01-01

    Recent results indicate that genome-wide association studies (GWAS) have the potential to explain much of the heritability of common complex phenotypes, but methods are lacking to reliably identify the remaining associated single nucleotide polymorphisms (SNPs). We applied stratified False...... Discovery Rate (sFDR) methods to leverage genic enrichment in GWAS summary statistics data to uncover new loci likely to replicate in independent samples. Specifically, we use linkage disequilibrium-weighted annotations for each SNP in combination with nominal p-values to estimate the True Discovery Rate...... (TDR = 1-FDR) for strata determined by different genic categories. We show a consistent pattern of enrichment of polygenic effects in specific annotation categories across diverse phenotypes, with the greatest enrichment for SNPs tagging regulatory and coding genic elements, little enrichment in...

  7. A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study.

    Tintle, N L; Pottala, J V; Lacey, S; Ramachandran, V; Westra, J; Rogers, A; Clark, J; Olthoff, B; Larson, M; Harris, W; Shearer, G C

    2015-03-01

    Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations (pFADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8-14% of the variation in 3 high abundance (>11%) fatty acids, but only 1-3% in 4 low abundance (genes influence tissue fatty acid content and pathways modulated by fatty acids. PMID:25500335

  8. Genome-wide detection of selection and other evolutionary forces

    Xu, Zhuofei; Zhou, Rui

    As is well known, pathogenic microbes evolve rapidly to escape from the host immune system and antibiotics. Genetic variations among microbial populations occur frequently during the long-term pathogen–host evolutionary arms race, and individual mutation beneficial for the fitness can be fixed...... preferentially. Many recent comparative genomics studies have pointed out the importance of selective forces in the molecular evolution of bacterial pathogens. The public availability of large-scale next-generation sequencing data and many state-of-the-art statistical methods of molecular evolution enable us to...... scan genome-wide alignments for evidence of positive Darwinian selection, recombination, and other evolutionary forces operating on the coding regions. In this chapter, we describe an integrative analysis pipeline and its application to tracking featured evolutionary trajectories on the genome of an...

  9. Genome-wide transcriptional reprogramming under drought stress

    Chen, Hao

    2012-01-01

    Soil water deficit is one of the major factors limiting plant productivity. Plants cope with this adverse environmental condition by coordinating the up- or downregulation of an array of stress responsive genes. Reprogramming the expression of these genes leads to rebalanced development and growth that are in concert with the reduced water availability and that ultimately confer enhanced stress tolerance. Currently, several techniques have been employed to monitor genome-wide transcriptional reprogramming under drought stress. The results from these high throughput studies indicate that drought stress-induced transcriptional reprogramming is dynamic, has temporal and spatial specificity, and is coupled with the circadian clock and phytohormone signaling pathways. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.

  10. AID/APOBEC cytosine deaminase induces genome-wide kataegis

    Lada Artem G

    2012-12-01

    Full Text Available Abstract Clusters of localized hypermutation in human breast cancer genomes, named “kataegis” (from the Greek for thunderstorm, are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events. Reviewers This article was reviewed by: Professor Sandor Pongor, Professor Shamil R. Sunyaev, and Dr Vladimir Kuznetsov.

  11. A comparison of multivariate genome-wide association methods

    Galesloot, Tessel E; Van Steen, Kristel; Kiemeney, Lambertus A L M;

    2014-01-01

    Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six...... methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three...... correlation. We compared the power of the methods using empirically fixed significance thresholds (α = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power...

  12. Quantitative prediction of genome-wide resource allocation in bacteria.

    Goelzer, Anne; Muntel, Jan; Chubukov, Victor; Jules, Matthieu; Prestel, Eric; Nölker, Rolf; Mariadassou, Mahendra; Aymerich, Stéphane; Hecker, Michael; Noirot, Philippe; Becher, Dörte; Fromion, Vincent

    2015-11-01

    Predicting resource allocation between cell processes is the primary step towards decoding the evolutionary constraints governing bacterial growth under various conditions. Quantitative prediction at genome-scale remains a computational challenge as current methods are limited by the tractability of the problem or by simplifying hypotheses. Here, we show that the constraint-based modeling method Resource Balance Analysis (RBA), calibrated using genome-wide absolute protein quantification data, accurately predicts resource allocation in the model bacterium Bacillus subtilis for a wide range of growth conditions. The regulation of most cellular processes is consistent with the objective of growth rate maximization except for a few suboptimal processes which likely integrate more complex objectives such as coping with stressful conditions and survival. As a proof of principle by using simulations, we illustrated how calibrated RBA could aid rational design of strains for maximizing protein production, offering new opportunities to investigate design principles in prokaryotes and to exploit them for biotechnological applications. PMID:26498510

  13. Chapter 10: Mining genome-wide genetic markers.

    Xiang Zhang

    Full Text Available Genome-wide association study (GWAS aims to discover genetic factors underlying phenotypic traits. The large number of genetic factors poses both computational and statistical challenges. Various computational approaches have been developed for large scale GWAS. In this chapter, we will discuss several widely used computational approaches in GWAS. The following topics will be covered: (1 An introduction to the background of GWAS. (2 The existing computational approaches that are widely used in GWAS. This will cover single-locus, epistasis detection, and machine learning methods that have been recently developed in biology, statistic, and computer science communities. This part will be the main focus of this chapter. (3 The limitations of current approaches and future directions.

  14. Genome-wide significant risk associations for mucinous ovarian carcinoma

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan;

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2......q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at...

  15. Detection of MDR1 single nucleotide polymorphisms C3435T and G2677T using real-time polymerase chain reaction: MDR1 single nucleotide polymorphism genotyping assay

    Song, Pengfei; Li, Shen; Meibohm, Bernd; Gaber, A. Osama; Honaker, Marsha R.; Kotb, Malak; Yates, Charles R.

    2002-01-01

    The objective of this study was to develop a real-time polymerase chain reaction (PCR) method to detect MDR1 (human multidrug resistance gene) single nucleotide polymorphisms (SNPs) C3435T and G2677T. C3435T and G2677T are linked to MDR1*2, which is associated with enhanced efflux activity in vitro. Using the Smart Cycler, an allele-specific real-time PCR-based genotyping method was developed to detect C3435T and G2677T. The MDR1 genotype of human genomic DNA templates was determined by direc...

  16. Genome-wide association studies in asthma: progress and pitfalls

    March ME

    2015-01-01

    Full Text Available Michael E March,1 Patrick MA Sleiman,1,2 Hakon Hakonarson1,2 1Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine. Keywords: asthma, genetics, GWAS, pharmacogenetics, biomarkers

  17. Genome-wide DNA methylation scan in major depressive disorder.

    Sarven Sabunciyan

    Full Text Available While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD, epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003, and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16, which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.

  18. Genome wide association identifies novel loci involved in fungal communication.

    Palma-Guerrero, Javier; Hall, Charles R; Kowbel, David; Welch, Juliet; Taylor, John W; Brem, Rachel B; Glass, N Louise

    2013-01-01

    Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power

  19. Quantitative trait loci for rice blast resistance detected in a local rice breeding population by genome-wide association mapping.

    Shinada, Hiroshi; Yamamoto, Toshio; Sato, Hirokazu; Yamamoto, Eiji; Hori, Kiyosumi; Yonemaru, Junichi; Sato, Takashi; Fujino, Kenji

    2015-12-01

    Plant breeding programs aim to develop cultivars with high adaptability to the specific conditions in a local region. As a result, unique genes and gene combinations have been accumulated in local elite breeding populations during the long history of plant breeding. Genetic analyses on such genes and combinations may be useful for developing new cultivars with more-desirable agronomic traits. Here, we attempted to detect quantitative trait loci (QTL) for rice blast resistance (BR) using a local breeding rice population from Hokkaido, Japan. Using genotyping data on single nucleotide polymorphisms and simple sequence repeat markers distributed throughout the whole genomic region, we detected genetic regions associated with phenotypic variation in BR by a genome-wide association mapping study (GWAS). An additional association analysis using other breeding cultivars verified the effect and inheritance of the associated region. Furthermore, the existence of a gene for BR in the associated region was confirmed by QTL mapping. The results from these studies enabled us to estimate potential of the Hokkaido rice population as a gene pool for improving BR. The results of this study could be useful for developing novel cultivars with vigorous BR in rice breeding programs. PMID:26719741

  20. Genome-wide association reveals genetic basis for the propensity to migrate in wild populations of rainbow and steelhead trout.

    Hecht, Benjamin C; Campbell, Nathan R; Holecek, Dean E; Narum, Shawn R

    2013-06-01

    Little is known of the genetic basis of migration despite the ecological benefits migratory species provide to their communities and their rapid global decline due to anthropogenic disturbances in recent years. Using next-generation sequencing of restriction-site-associated DNA (RAD) tags, we genotyped thousands of single nucleotide polymorphisms (SNPs) in two wild populations of migratory steelhead and resident rainbow trout (Oncorhynchus mykiss) from the Pacific Northwest of the United States. One population maintains a connection to the sea, whereas the other population has been sequestered from its access to the ocean for more than 50 years by a hydropower dam. Here we performed a genome-wide association study to identify 504 RAD SNP markers from several genetic regions that were associated with the propensity to migrate both within and between the populations. Our results corroborate those in previous quantitative trait loci studies and provide evidence for additional loci associated with this complex migratory life history. Our results suggest a complex multi-genic basis with several loci of small effect distributed throughout the genome contributing to migration in this species. We also determined that despite being sequestered for decades, the landlocked population continues to harbour genetic variation associated with a migratory life history and ATPase activity. Furthermore, we demonstrate the utility of genotyping-by-sequencing and how RAD-tag SNP data can be readily compared between studies to investigate migration within this species. PMID:23106605

  1. ChIP on SNP-chip for genome-wide analysis of human histone H4 hyperacetylation

    Porter Christopher J

    2007-09-01

    Full Text Available Abstract Background SNP microarrays are designed to genotype Single Nucleotide Polymorphisms (SNPs. These microarrays report hybridization of DNA fragments and therefore can be used for the purpose of detecting genomic fragments. Results Here, we demonstrate that a SNP microarray can be effectively used in this way to perform chromatin immunoprecipitation (ChIP on chip as an alternative to tiling microarrays. We illustrate this novel application by mapping whole genome histone H4 hyperacetylation in human myoblasts and myotubes. We detect clusters of hyperacetylated histone H4, often spanning across up to 300 kilobases of genomic sequence. Using complementary genome-wide analyses of gene expression by DNA microarray we demonstrate that these clusters of hyperacetylated histone H4 tend to be associated with expressed genes. Conclusion The use of a SNP array for a ChIP-on-chip application (ChIP on SNP-chip will be of great value to laboratories whose interest is the determination of general rules regarding the relationship of specific chromatin modifications to transcriptional status throughout the genome and to examine the asymmetric modification of chromatin at heterozygous loci.

  2. Influence of Feature Encoding and Choice of Classifier on Disease Risk Prediction in Genome-Wide Association Studies.

    Florian Mittag

    Full Text Available Various attempts have been made to predict the individual disease risk based on genotype data from genome-wide association studies (GWAS. However, most studies only investigated one or two classification algorithms and feature encoding schemes. In this study, we applied seven different classification algorithms on GWAS case-control data sets for seven different diseases to create models for disease risk prediction. Further, we used three different encoding schemes for the genotypes of single nucleotide polymorphisms (SNPs and investigated their influence on the predictive performance of these models. Our study suggests that an additive encoding of the SNP data should be the preferred encoding scheme, as it proved to yield the best predictive performances for all algorithms and data sets. Furthermore, our results showed that the differences between most state-of-the-art classification algorithms are not statistically significant. Consequently, we recommend to prefer algorithms with simple models like the linear support vector machine (SVM as they allow for better subsequent interpretation without significant loss of accuracy.

  3. Genome-Wide Association Mapping of Barley Yellow Dwarf Virus Tolerance in Spring Oat (Avena sativa L.)

    Foresman, Bradley J.; Oliver, Rebekah E.; Jackson, Eric W.; Chao, Shiaoman; Arruda, Marcio P.; Kolb, Frederic L.

    2016-01-01

    Barley yellow dwarf viruses (BYDVs) are responsible for the disease barley yellow dwarf (BYD) and affect many cereals including oat (Avena sativa L.). Until recently, the molecular marker technology in oat has not allowed for many marker-trait association studies to determine the genetic mechanisms for tolerance. A genome-wide association study (GWAS) was performed on 428 spring oat lines using a recently developed high-density oat single nucleotide polymorphism (SNP) array as well as a SNP-based consensus map. Marker-trait associations were performed using a Q-K mixed model approach to control for population structure and relatedness. Six significant SNP-trait associations representing two QTL were found on chromosomes 3C (Mrg17) and 18D (Mrg04). This is the first report of BYDV tolerance QTL on chromosome 3C (Mrg17) and 18D (Mrg04). Haplotypes using the two QTL were evaluated and distinct classes for tolerance were identified based on the number of favorable alleles. A large number of lines carrying both favorable alleles were observed in the panel. PMID:27175781

  4. Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery.

    Amanda A Fox

    Full Text Available BACKGROUND: Postoperative ventricular dysfunction (VnD occurs in 9-20% of coronary artery bypass graft (CABG surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. METHODS: A genome-wide association study identified single nucleotide polymorphisms (SNPs associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. RESULTS: Over 100 SNPs were associated with VnD (P2.1 of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

  5. Genome-wide association study identifies loci and candidate genes for meat quality traits in Simmental beef cattle.

    Xia, Jiangwei; Qi, Xin; Wu, Yang; Zhu, Bo; Xu, Lingyang; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Gao, Huijiang

    2016-06-01

    Improving meat quality is the best way to enhance profitability and strengthen competitiveness in beef industry. Identification of genetic variants that control beef quality traits can help breeders design optimal breeding programs to achieve this goal. We carried out a genome-wide association study for meat quality traits in 1141 Simmental cattle using the Illumina Bovine HD 770K SNP array to identify the candidate genes and genomic regions associated with meat quality traits for beef cattle, including fat color, meat color, marbling score, longissimus muscle area, and shear force. In our study, we identified twenty significant single-nucleotide polymorphisms (SNPs) (p five meat quality traits. Notably, we observed several SNPs were in or near eleven genes which have been reported previously, including TMEM236, SORL1, TRDN, S100A10, AP2S1, KCTD16, LOC506594, DHX15, LAMA4, PREX1, and BRINP3. We identified a haplotype block on BTA13 containing five significant SNPs associated with fat color trait. We also found one of 19 SNPs was associated with multiple traits (shear force and longissimus muscle area) on BTA7. Our results offer valuable insights to further explore the potential mechanism of meat quality traits in Simmental beef cattle. PMID:27126640

  6. Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children.

    Hong, Xiumei; Hao, Ke; Ladd-Acosta, Christine; Hansen, Kasper D; Tsai, Hui-Ju; Liu, Xin; Xu, Xin; Thornton, Timothy A; Caruso, Deanna; Keet, Corinne A; Sun, Yifei; Wang, Guoying; Luo, Wei; Kumar, Rajesh; Fuleihan, Ramsay; Singh, Anne Marie; Kim, Jennifer S; Story, Rachel E; Gupta, Ruchi S; Gao, Peisong; Chen, Zhu; Walker, Sheila O; Bartell, Tami R; Beaty, Terri H; Fallin, M Daniele; Schleimer, Robert; Holt, Patrick G; Nadeau, Kari Christine; Wood, Robert A; Pongracic, Jacqueline A; Weeks, Daniel E; Wang, Xiaobin

    2015-01-01

    Food allergy (FA) affects 2%-10% of US children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk and egg) in 2,759 US participants (1,315 children and 1,444 parents) from the Chicago Food Allergy Study, and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (P=5.5 × 10(-8)) and rs9275596 (P=6.8 × 10(-10)), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (P<5 × 10(-8)), and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region probably poses significant genetic risk for PA. PMID:25710614

  7. Goldsurfer2 (Gs2: A comprehensive tool for the analysis and visualization of genome wide association studies

    Barnes Michael R

    2008-03-01

    Full Text Available Abstract Background Genome wide association (GWA studies are now being widely undertaken aiming to find the link between genetic variations and common diseases. Ideally, a well-powered GWA study will involve the measurement of hundreds of thousands of single nucleotide polymorphisms (SNPs in thousands of individuals. The sheer volume of data generated by these experiments creates very high analytical demands. There are a number of important steps during the analysis of such data, many of which may present severe bottlenecks. The data need to be imported and reviewed to perform initial quality control (QC before proceeding to association testing. Evaluation of results may involve further statistical analysis, such as permutation testing, or further QC of associated markers, for example, reviewing raw genotyping intensities. Finally significant associations need to be prioritised using functional and biological interpretation methods, browsing available biological annotation, pathway information and patterns of linkage disequilibrium (LD. Results We have developed an interactive and user-friendly graphical application to be used in all steps in GWA projects from initial data QC and analysis to biological evaluation and validation of results. The program is implemented in Java and can be used on all platforms. Conclusion Very large data sets (e.g. 500 k markers and 5000 samples can be quality assessed, rapidly analysed and integrated with genomic sequence information. Candidate SNPs can be selected and functionally evaluated.

  8. Characterization of genome-wide SNPs for the water flea Daphnia pulicaria generated by genotyping-by-sequencing (GBS)

    Muñoz, Joaquín; Chaturvedi, Anurag; De Meester, Luc; Weider, Lawrence J.

    2016-01-01

    The keystone aquatic herbivore Daphnia has been studied for more than 150 years in the context of evolution, ecology and ecotoxicology. Although it is rapidly becoming an emergent model for environmental and population genomics, there have been limited genome-wide level studies in natural populations. We report a unique resource of novel Single Nucleotide Polymorphic (SNP) markers for Daphnia pulicaria using the reduction in genomic complexity with the restriction enzymes approach, genotyping-by-sequencing. Using the genome of D. pulex as a reference, SNPs were scored for 53 clones from five natural populations that varied in lake trophic status. Our analyses resulted in 32,313 highly confident and bi-allelic SNP markers. 1,364 outlier SNPs were mapped on the annotated D. pulex genome, which identified 2,335 genes, including 565 within functional genes. Out of 885 EuKaryotic Orthologous Groups that we found from outlier SNPs, 294 were involved in three metabolic and four regulatory pathways. Bayesian-clustering analyses showed two distinct population clusters representing the possible combined effects of geography and lake trophic status. Our results provide an invaluable tool for future population genomics surveys in Daphnia targeting informative regions related to physiological processes that can be linked to the ecology of this emerging eco-responsive taxon. PMID:27346179

  9. Genome-wide high-resolution mapping of UV-induced mitotic recombination events in Saccharomyces cerevisiae.

    Yi Yin

    2013-10-01

    Full Text Available In the yeast Saccharomyces cerevisiae and most other eukaryotes, mitotic recombination is important for the repair of double-stranded DNA breaks (DSBs. Mitotic recombination between homologous chromosomes can result in loss of heterozygosity (LOH. In this study, LOH events induced by ultraviolet (UV light are mapped throughout the genome to a resolution of about 1 kb using single-nucleotide polymorphism (SNP microarrays. UV doses that have little effect on the viability of diploid cells stimulate crossovers more than 1000-fold in wild-type cells. In addition, UV stimulates recombination in G1-synchronized cells about 10-fold more efficiently than in G2-synchronized cells. Importantly, at high doses of UV, most conversion events reflect the repair of two sister chromatids that are broken at approximately the same position whereas at low doses, most conversion events reflect the repair of a single broken chromatid. Genome-wide mapping of about 380 unselected crossovers, break-induced replication (BIR events, and gene conversions shows that UV-induced recombination events occur throughout the genome without pronounced hotspots, although the ribosomal RNA gene cluster has a significantly lower frequency of crossovers.

  10. Genome wide analysis indicates genes for basement membrane and cartilage matrix proteins as candidates for hip dysplasia in Labrador Retrievers.

    Lavrijsen, Ineke C M; Leegwater, Peter A J; Martin, Alan J; Harris, Stephen J; Tryfonidou, Marianna A; Heuven, Henri C M; Hazewinkel, Herman A W

    2014-01-01

    Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs) in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ(2) statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (phip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia. PMID:24498183

  11. Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans.

    Chen, Guanjie; Bentley, Amy; Adeyemo, Adebowale; Shriner, Daniel; Zhou, Jie; Doumatey, Ayo; Huang, Hanxia; Ramos, Edward; Erdos, Michael; Gerry, Norman; Herbert, Alan; Christman, Michael; Rotimi, Charles

    2012-10-15

    Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes. PMID:22791750

  12. A validated genome wide association study to breed cattle adapted to an environment altered by climate change.

    Hayes, Ben J; Bowman, Phil J; Chamberlain, Amanda J; Savin, Keith; van Tassell, Curt P; Sonstegard, Tad S; Goddard, Mike E

    2009-01-01

    Continued production of food in areas predicted to be most affected by climate change, such as dairy farming regions of Australia, will be a major challenge in coming decades. Along with rising temperatures and water shortages, scarcity of inputs such as high energy feeds is predicted. With the motivation of selecting cattle adapted to these changing environments, we conducted a genome wide association study to detect DNA markers (single nucleotide polymorphisms) associated with the sensitivity of milk production to environmental conditions. To do this we combined historical milk production and weather records with dense marker genotypes on dairy sires with many daughters milking across a wide range of production environments in Australia. Markers associated with sensitivity of milk production to feeding level and sensitivity of milk production to temperature humidity index on chromosome nine and twenty nine respectively were validated in two independent populations, one a different breed of cattle. As the extent of linkage disequilibrium across cattle breeds is limited, the underlying causative mutations have been mapped to a small genomic interval containing two promising candidate genes. The validated marker panels we have reported here will aid selection for high milk production under anticipated climate change scenarios, for example selection of sires whose daughters will be most productive at low levels of feeding. PMID:19688089

  13. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.

    Ramagopalan, Sreeram V; Heger, Andreas; Berlanga, Antonio J; Maugeri, Narelle J; Lincoln, Matthew R; Burrell, Amy; Handunnetthi, Lahiru; Handel, Adam E; Disanto, Giulio; Orton, Sarah-Michelle; Watson, Corey T; Morahan, Julia M; Giovannoni, Gavin; Ponting, Chris P; Ebers, George C; Knight, Julian C

    2010-10-01

    Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases. PMID:20736230

  14. Genome-Wide SNP Analysis of Southern African Populations Provides New Insights into the Dispersal of Bantu-Speaking Groups

    González-Santos, Miguel; Montinaro, Francesco; Oosthuizen, Ockie; Oosthuizen, Erica; Busby, George B.J.; Anagnostou, Paolo; Destro-Bisol, Giovanni; Pascali, Vincenzo; Capelli, Cristian

    2015-01-01

    The expansion of Bantu-speaking agropastoralist populations had a great impact on the genetic, linguistic, and cultural variation of sub-Saharan Africa. It is generally accepted that Bantu languages originated in an area around the present border between Cameroon and Nigeria approximately 5,000 years ago, from where they spread South and East becoming the largest African linguistic branch. The demic consequences of this event are reflected in the relatively high genetic homogeneity observed across most of sub-Saharan Africa populations. In this work, we explored genome-wide single nucleotide polymorphism data from 28 populations to characterize the genetic components present in sub-Saharan African populations. Combining novel data from four Southern African populations with previously published results, we reject the hypothesis that the “non-Bantu” genetic component reported in South-Eastern Africa (Mozambique) reflects extensive gene flow between incoming agriculturalist and resident hunter-gatherer communities. We alternatively suggest that this novel component is the result of demographic dynamics associated with the Bantu dispersal. PMID:26363465

  15. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

    Background and purpose: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2 years after radiotherapy. Materials and methods: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. Results: Quantile–quantile plots show more associations at the P < 5 × 10−7 level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. Conclusions: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable

  16. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels.

    Sun, Qi; Cornelis, Marilyn C; Kraft, Peter; Qi, Lu; van Dam, Rob M; Girman, Cynthia J; Laurie, Cathy C; Mirel, Daniel B; Gong, Huizi; Sheu, Chau-Chyun; Christiani, David C; Hunter, David J; Mantzoros, Christos S; Hu, Frank B

    2010-05-01

    Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P rs1137101), rs2767485, rs1751492 and rs4655555 remained associated with sOB-R levels at the 0.05 level (P = 9.1 x 10(-9), 0.0105 and 0.0267, respectively) after adjustment for other univariately associated SNPs in a forward selection procedure. Significant associations with these SNPs were replicated in an independent sample of young males (n = 875) residing in Cyprus (P < 1 x 10(-4)). These data provide novel evidence revealing the role of polymorphisms in LEPR in modulating plasma levels of sOB-R and may further our understanding of the complex relationships among leptin, leptin receptor and diabetes-related traits. PMID:20167575

  17. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.

    Emiko Noguchi

    2011-07-01

    Full Text Available Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs showing strong associations (P<1×10(-8 in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls and in Korean samples (835 cases and 421 controls. SNP rs987870, located between HLA-DPA1 and HLA-DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined = 2.3×10(-10, odds ratio [OR] = 1.40. HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5×10(-10, OR = 1.52, and DPB1*0901: P = 2.0×10(-7, OR = 1.49. Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations.

  18. The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature

    Frackelton Edward C

    2010-06-01

    Full Text Available Abstract Background Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies. Methods To examine 51 single nucleotide polymorphisms (SNPs corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort. Results Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score. Conclusion Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood.

  19. Genome-wide association analysis and differential expression analysis of resistance to Sclerotinia stem rot in Brassica napus.

    Wei, Lijuan; Jian, Hongju; Lu, Kun; Filardo, Fiona; Yin, Nengwen; Liu, Liezhao; Qu, Cunmin; Li, Wei; Du, Hai; Li, Jiana

    2016-06-01

    Brassica napus is one of the most important oil crops in the world, and stem rot caused by the fungus Sclerotinia sclerotiorum results in major losses in yield and quality. To elucidate resistance genes and pathogenesis-related genes, genome-wide association analysis of 347 accessions was performed using the Illumina 60K Brassica SNP (single nucleotide polymorphism) array. In addition, the detached stem inoculation assay was used to select five highly resistant (R) and susceptible (S) B. napus lines, 48 h postinoculation with S. sclerotiorum for transcriptome sequencing. We identified 17 significant associations for stem resistance on chromosomes A8 and C6, five of which were on A8 and 12 on C6. The SNPs identified on A8 were located in a 409-kb haplotype block, and those on C6 were consistent with previous QTL mapping efforts. Transcriptome analysis suggested that S. sclerotiorum infection activates the immune system, sulphur metabolism, especially glutathione (GSH) and glucosinolates in both R and S genotypes. Genes found to be specific to the R genotype related to the jasmonic acid pathway, lignin biosynthesis, defence response, signal transduction and encoding transcription factors. Twenty-four genes were identified in both the SNP-trait association and transcriptome sequencing analyses, including a tau class glutathione S-transferase (GSTU) gene cluster. This study provides useful insight into the molecular mechanisms underlying the plant's response to S. sclerotiorum. PMID:26563848

  20. A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease.

    Hardin, M; Cho, M H; McDonald, M-L; Wan, E; Lomas, D A; Coxson, H O; MacNee, W; Vestbo, J; Yates, J C; Agusti, A; Calverley, P M A; Celli, B; Crim, C; Rennard, S; Wouters, E; Bakke, P; Bhatt, S P; Kim, V; Ramsdell, J; Regan, E A; Make, B J; Hokanson, J E; Crapo, J D; Beaty, T H; Hersh, C P

    2016-08-01

    Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65. PMID:26503814

  1. Evaluation of results from genome-wide studies of language and reading in a novel independent dataset.

    Carrion-Castillo, A; van Bergen, E; Vino, A; van Zuijen, T; de Jong, P F; Francks, C; Fisher, S E

    2016-07-01

    Recent genome-wide association scans (GWAS) for reading and language abilities have pin-pointed promising new candidate loci. However, the potential contributions of these loci remain to be validated. In this study, we tested 17 of the most significantly associated single nucleotide polymorphisms (SNPs) from these GWAS studies (P Literacy Abilities. This dataset comprised 483 children from 307 nuclear families and 505 adults (including parents of participating children), and provided adequate statistical power to detect the effects that were previously reported. The following measures of reading and language performance were collected: word reading fluency, nonword reading fluency, phonological awareness and rapid automatized naming. Two SNPs (rs12636438 and rs7187223) were associated with performance in multivariate and univariate testing, but these did not remain significant after correction for multiple testing. Another SNP (rs482700) was only nominally associated in the multivariate test. For the rest of the SNPs, we did not find supportive evidence of association. The findings may reflect differences between our study and the previous investigations with respect to the language of testing, the exact tests used and the recruitment criteria. Alternatively, most of the prior reported associations may have been false positives. A larger scale GWAS meta-analysis than those previously performed will likely be required to obtain robust insights into the genomic architecture underlying reading and language. PMID:27198479

  2. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

    Mosley, J D; Shaffer, C M; Van Driest, S L; Weeke, P E; Wells, Q S; Karnes, J H; Velez Edwards, D R; Wei, W-Q; Teixeira, P L; Bastarache, L; Crawford, D C; Li, R; Manolio, T A; Bottinger, E P; McCarty, C A; Linneman, J G; Brilliant, M H; Pacheco, J A; Thompson, W; Chisholm, R L; Jarvik, G P; Crosslin, D R; Carrell, D S; Baldwin, E; Ralston, J; Larson, E B; Grafton, J; Scrol, A; Jouni, H; Kullo, I J; Tromp, G; Borthwick, K M; Kuivaniemi, H; Carey, D J; Ritchie, M D; Bradford, Y; Verma, S S; Chute, C G; Veluchamy, A; Siddiqui, M K; Palmer, C N A; Doney, A; MahmoudPour, S H; Maitland-van der Zee, A H; Morris, A D; Denny, J C; Roden, D M

    2016-06-01

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk. PMID:26169577

  3. Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice

    Background and purpose: To identify genes which influence the fibrotic response to thoracic cavity radiotherapy, we combined a genome wide single nucleotide polymorphism (SNP) association evaluation of inbred strain response with prior linkage and gene expression data. Material and methods: Mice were exposed to 18 Gy whole thorax irradiation and survival, bronchoalveolar cell differential, and histological alveolitis and fibrosis phenotypes were determined. Association analyses were completed with 1.8 million SNPs in single markers and haplotypes. Results: Nine strains developed significant fibrosis and 11 strains succumbed to alveolitis only or alveolitis with minimal fibrosis. Post irradiation survival time (p −6; by permutation test), with the most significant SNP within a conserved non-coding region downstream of cell adhesion molecule 1 (Cadm1). Haplotype and SNP analyses performed within previously-identified loci revealed additional genes containing SNPs associated with fibrosis including Slamf6 and Cdkn1a. Conclusion: Combining genomic approaches identified variation within specific genes which function in the tissue response to injury as associated with fibrosis following thoracic irradiation in mice.

  4. Incorporating prior knowledge to facilitate discoveries in a genome-wide association study on age-related macular degeneration

    Lee Wen-Chung

    2010-01-01

    Full Text Available Abstract Background Substantial genotyping data produced by current high-throughput technologies have brought opportunities and difficulties. With the number of single-nucleotide polymorphisms (SNPs going into millions comes the harsh challenge of multiple-testing adjustment. However, even with the false discovery rate (FDR control approach, a genome-wide association study (GWAS may still fall short of discovering any true positive gene, particularly when it has a relatively small sample size. Findings To counteract such a harsh multiple-testing penalty, in this report, we incorporate findings from previous linkage and association studies to re-analyze a GWAS on age-related macular degeneration. While previous Bonferroni correction and the traditional FDR approach detected only one significant SNP (rs380390, here we have been able to detect seven significant SNPs with an easy-to-implement prioritized subset analysis (PSA with the overall FDR controlled at 0.05. These include SNPs within three genes: CFH, CFHR4, and SGCD. Conclusions Based on the success of this example, we advocate using the simple method of PSA to facilitate discoveries in future GWASs.

  5. Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans

    Keaton, Jacob M.; Hellwege, Jacklyn N.; Ng, Maggie C. Y.; Palmer, Nicholette D.; Pankow, James S.; Fornage, Myriam; Wilson, James G.; Correa, Adolfo; Rasmussen-Torvik, Laura J.; Rotter, Jerome I.; Chen, Yii-Der I.; Taylor, Kent D.; Rich, Stephen S.; Wagenknecht, Lynne E.; Freedman, Barry I.; Bowden, Donald W.

    2016-01-01

    Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci. PMID:27448167

  6. A genome-wide association study identifies a gene network of ADAMTS genes in the predisposition to pediatric stroke.

    Arning, Astrid; Hiersche, Milan; Witten, Anika; Kurlemann, Gerhard; Kurnik, Karin; Manner, Daniela; Stoll, Monika; Nowak-Göttl, Ulrike

    2012-12-20

    Pediatric stroke is a rare but highly penetrant disease with a strong genetic background. Although there are an increasing number of genome-wide association studies (GWASs) for stroke in adults, such studies for stroke of pediatric onset are lacking. Here we report the results of the first GWAS on pediatric stroke using a large cohort of 270 family-based trios. GWAS was performed using the Illumina 370 CNV single nucleotide polymorphisms array and analyzed using the transmission disequilibrium test as implemented in PLINK. An enrichment analysis was performed to identify additional true association signals among lower P value signals and searched for cumulatively associated genes within protein interaction data using dmGWAS. We observed clustering of association signals in 4 genes belonging to one family of metalloproteinases at high (ADAMTS12, P = 2.9 × 10(-6); ADAMTS2, P = 8.0 × 10(-6)) and moderate (ADAMTS13, P = 9.3 × 10(-4); ADAMTS17, P = 8.5 × 10(-4)) significance levels. Over-representation and gene-network analyses highlight the importance of the extracellular matrix in conjunction with members of the phosphoinositide and calcium signaling pathways in the susceptibility for pediatric stroke. Associated extracellular matrix components, such as ADAMTS proteins, in combination with misbalanced coagulation signals as unveiled by gene network analysis suggest a major role of postnatal vascular injury with subsequent thrombus formation as the leading cause of pediatric stroke. PMID:22990015

  7. Genome-wide association of coagulation properties, curd firmness modeling, protein percentage, and acidity in milk from Brown Swiss cows.

    Dadousis, C; Biffani, S; Cipolat-Gotet, C; Nicolazzi, E L; Rossoni, A; Santus, E; Bittante, G; Cecchinato, A

    2016-05-01

    Cheese production is increasing in many countries, and a desire toward genetic selection for milk coagulation properties in dairy cattle breeding exists. However, measurements of individual cheesemaking properties are hampered by high costs and labor, whereas traditional single-point milk coagulation properties (MCP) are sometimes criticized. Nevertheless, new modeling of the entire curd firmness and syneresis process (CFt equation) offers new insight into the cheesemaking process. Moreover, identification of genomic regions regulating milk cheesemaking properties might enhance direct selection of individuals in breeding programs based on cheese ability rather than related milk components. Therefore, the objective of this study was to perform genome-wide association studies to identify genomic regions linked to traditional MCP and new CFt parameters, milk acidity (pH), and milk protein percentage. Milk and DNA samples from 1,043 Italian Brown Swiss cows were used. Milk pH and 3 MCP traits were grouped together to represent the MCP set. Four CFt equation parameters, 2 derived traits, and protein percentage were considered as the second group of traits (CFt set). Animals were genotyped with the Illumina SNP50 BeadChip v.2 (Illumina Inc., San Diego, CA). Multitrait animal models were used to estimate variance components. For genome-wide association studies, the genome-wide association using mixed model and regression-genomic control approach was used. In total, 106 significant marker traits associations and 66 single nucleotide polymorphisms were identified on 12 chromosomes (1, 6, 9, 11, 13, 15, 16, 19, 20, 23, 26, and 28). Sharp peaks were detected at 84 to 88 Mbp on Bos taurus autosome (BTA) 6, with a peak at 87.4 Mbp in the region harboring the casein genes. Evidence of quantitative trait loci at 82.6 and 88.4 Mbp on the same chromosome was found. All chromosomes but BTA6, BTA11, and BTA28 were associated with only one trait. Only BTA6 was in common between MCP

  8. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  9. A Preliminary Genome-Wide Association Study of Acute Mountain Sickness Susceptibility in a Group of Nepalese Pilgrims Ascending to 4380 m.

    MacInnis, Martin J; Widmer, Nadia; Timulsina, Utsav; Subedi, Ankita; Siwakoti, Ashmita; Pandit, Bidur Prasad; Freeman, Michael G; Carter, Eric A; Manokhina, Irina; Thapa, Ghan Bahadur; Koehle, Michael S

    2015-12-01

    There is significant interindividual variation in acute mountain sickness (AMS) susceptibility in humans. To identify genes related to AMS susceptibility, we used a genome-wide association study (GWAS) to simultaneously test associations between genetic variants dispersed throughout the genome and the presence and severity of AMS. DNA samples were collected from subjects who ascended rapidly to Gosainkunda, Nepal (4380 m), as part of the 2005, 2010, and 2012 Janai Purnima festivals. The Lake Louise Score was used to measure AMS severity. The primary analysis was based on 99 male subjects (43 with AMS; 56 without AMS). Genotyping for the GWAS was performed using Infinium Human Core Exome Bead Chips (542,556 single-nucleotide polymorphisms were assayed), and validation genotyping was performed with pyrosequencing in two additional cohorts (n = 101 for each). In total, 270,389 single nucleotide polymorphisms (SNPs) passed quality control, and 4 SNPs (one intronic, three nonsynonymous) in the FAM149A gene were associated with AMS severity after correcting for multiple hypothesis testing (p = 1.8E-7); however, in the validation cohorts, FAM149A was not associated with the presence or severity of AMS. No other genes were associated with AMS susceptibility at the genome-wide level. Due to the large influence of environmental factors (i.e., ascent rate and altitude attained) and the difficulties associated with the AMS phenotype (i.e., low repeatability, nonspecific symptoms, potentially independent ailments), we suggest that future studies addressing the variation in the acute human hypoxia response should focus on objective responses to acute hypoxia instead of AMS. PMID:26600424

  10. Genome wide in silico SNP-tumor association analysis

    Carcinogenesis occurs, at least in part, due to the accumulation of mutations in critical genes that control the mechanisms of cell proliferation, differentiation and death. Publicly accessible databases contain millions of expressed sequence tag (EST) and single nucleotide polymorphism (SNP) records, which have the potential to assist in the identification of SNPs overrepresented in tumor tissue. An in silico SNP-tumor association study was performed utilizing tissue library and SNP information available in NCBI's dbEST (release 092002) and dbSNP (build 106). A total of 4865 SNPs were identified which were present at higher allele frequencies in tumor compared to normal tissues. A subset of 327 (6.7%) SNPs induce amino acid changes to the protein coding sequences. This approach identified several SNPs which have been previously associated with carcinogenesis, as well as a number of SNPs that now warrant further investigation This novel in silico approach can assist in prioritization of genes and SNPs in the effort to elucidate the genetic mechanisms underlying the development of cancer

  11. Genome-Wide Analysis and Characterization of Aux/IAA Family Genes in Brassica rapa.

    Parameswari Paul

    Full Text Available Auxins are the key players in plant growth development involving leaf formation, phototropism, root, fruit and embryo development. Auxin/Indole-3-Acetic Acid (Aux/IAA are early auxin response genes noted as transcriptional repressors in plant auxin signaling. However, many studies focus on Aux/ARF gene families and much less is known about the Aux/IAA gene family in Brassica rapa (B. rapa. Here we performed a comprehensive genome-wide analysis and identified 55 Aux/IAA genes in B. rapa using four conserved motifs of Aux/IAA family (PF02309. Chromosomal mapping of the B. rapa Aux/IAA (BrIAA genes facilitated understanding cluster rearrangement of the crucifer building blocks in the genome. Phylogenetic analysis of BrIAA with Arabidopsis thaliana, Oryza sativa and Zea mays identified 51 sister pairs including 15 same species (BrIAA-BrIAA and 36 cross species (BrIAA-AtIAA IAA genes. Among the 55 BrIAA genes, expression of 43 and 45 genes were verified using Genebank B. rapa ESTs and in home developed microarray data from mature leaves of Chiifu and RcBr lines. Despite their huge morphological difference, tissue specific expression analysis of BrIAA genes between the parental lines Chiifu and RcBr showed that the genes followed a similar pattern of expression during leaf development and a different pattern during bud, flower and siliqua development stages. The response of the BrIAA genes to abiotic and auxin stress at different time intervals revealed their involvement in stress response. Single Nucleotide Polymorphisms between IAA genes of reference genome Chiifu and RcBr were focused and identified. Our study examines the scope of conservation and divergence of Aux/IAA genes and their structures in B. rapa. Analyzing the expression and structural variation between two parental lines will significantly contribute to functional genomics of Brassica crops and we belive our study would provide a foundation in understanding the Aux/IAA genes in B. rapa.

  12. Genome-Wide Analysis and Characterization of Aux/IAA Family Genes in Brassica rapa.

    Paul, Parameswari; Dhandapani, Vignesh; Rameneni, Jana Jeevan; Li, Xiaonan; Sivanandhan, Ganesan; Choi, Su Ryun; Pang, Wenxing; Im, Subin; Lim, Yong Pyo

    2016-01-01

    Auxins are the key players in plant growth development involving leaf formation, phototropism, root, fruit and embryo development. Auxin/Indole-3-Acetic Acid (Aux/IAA) are early auxin response genes noted as transcriptional repressors in plant auxin signaling. However, many studies focus on Aux/ARF gene families and much less is known about the Aux/IAA gene family in Brassica rapa (B. rapa). Here we performed a comprehensive genome-wide analysis and identified 55 Aux/IAA genes in B. rapa using four conserved motifs of Aux/IAA family (PF02309). Chromosomal mapping of the B. rapa Aux/IAA (BrIAA) genes facilitated understanding cluster rearrangement of the crucifer building blocks in the genome. Phylogenetic analysis of BrIAA with Arabidopsis thaliana, Oryza sativa and Zea mays identified 51 sister pairs including 15 same species (BrIAA-BrIAA) and 36 cross species (BrIAA-AtIAA) IAA genes. Among the 55 BrIAA genes, expression of 43 and 45 genes were verified using Genebank B. rapa ESTs and in home developed microarray data from mature leaves of Chiifu and RcBr lines. Despite their huge morphological difference, tissue specific expression analysis of BrIAA genes between the parental lines Chiifu and RcBr showed that the genes followed a similar pattern of expression during leaf development and a different pattern during bud, flower and siliqua development stages. The response of the BrIAA genes to abiotic and auxin stress at different time intervals revealed their involvement in stress response. Single Nucleotide Polymorphisms between IAA genes of reference genome Chiifu and RcBr were focused and identified. Our study examines the scope of conservation and divergence of Aux/IAA genes and their structures in B. rapa. Analyzing the expression and structural variation between two parental lines will significantly contribute to functional genomics of Brassica crops and we belive our study would provide a foundation in understanding the Aux/IAA genes in B. rapa. PMID

  13. Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS

    Kim Nora

    2012-07-01

    Full Text Available Abstract Background It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO. Results We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs. Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the α = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the α = 0.05 level. A GO category was determined to replicate if that category was significant at the α = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, ‘Regulation of Cellular Component Organization and Biogenesis’, a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, ‘Actin Cytoskeleton’, a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. Conclusions Pathway

  14. Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood.

    Marie S Rye

    Full Text Available BACKGROUND: Otitis media (OM is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months and chronic OM with effusion (COME; MEE ≥ 3 months is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA = 8.3 × 10(-7 on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA = 2.2 × 10(-5 observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene = 2 × 10(-5 and BPIFA1 (P(Gene = 1.07 × 10(-4 in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA<10(-5 in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals from the Western Australian Family Study of Otitis Media (WAFSOM. Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as

  15. RS-SNP: a random-set method for genome-wide association studies

    Mukherjee Sayan

    2011-03-01

    Full Text Available Abstract Background The typical objective of Genome-wide association (GWA studies is to identify single-nucleotide polymorphisms (SNPs and corresponding genes with the strongest evidence of association (the 'most-significant SNPs/genes' approach. Borrowing ideas from micro-array data analysis, we propose a new method, named RS-SNP, for detecting sets of genes enriched in SNPs moderately associated to the phenotype. RS-SNP assesses whether the number of significant SNPs, with p-value P ≤ α, belonging to a given SNP set is statistically significant. The rationale of proposed method is that two kinds of null hypotheses are taken into account simultaneously. In the first null model the genotype and the phenotype are assumed to be independent random variables and the null distribution is the probability of the number of significant SNPs in greater than observed by chance. The second null model assumes the number of significant SNPs in depends on the size of and not on the identity of the SNPs in . Statistical significance is assessed using non-parametric permutation tests. Results We applied RS-SNP to the Crohn's disease (CD data set collected by the Wellcome Trust Case Control Consortium (WTCCC and compared the results with GENGEN, an approach recently proposed in literature. The enrichment analysis using RS-SNP and the set of pathways contained in the MSigDB C2 CP pathway collection highlighted 86 pathways rich in SNPs weakly associated to CD. Of these, 47 were also indicated to be significant by GENGEN. Similar results were obtained using the MSigDB C5 pathway collection. Many of the pathways found to be enriched by RS-SNP have a well-known connection to CD and often with inflammatory diseases. Conclusions The proposed method is a valuable alternative to other techniques for enrichment analysis of SNP sets. It is well founded from a theoretical and statistical perspective. Moreover, the experimental comparison with GENGEN highlights that it is

  16. Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees

    Coon Hilary

    2010-04-01

    Full Text Available Abstract Background Autism Spectrum Disorders (ASD are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability. Methods We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC methods to perform multilocus linkage analysis on large extended pedigrees. Results When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD = 2.91], 15q13.3 (HLOD = 3.64, and 13q12.3 (HLOD = 2.23. Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77. Additional positive quantitative results were seen on chromosomes 7, 9, and 19. Conclusions The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis

  17. A genome wide association study for backfat thickness in Italian Large White pigs highlights new regions affecting fat deposition including neuronal genes

    Fontanesi Luca

    2012-11-01

    Full Text Available Abstract Background Carcass fatness is an important trait in most pig breeding programs. Following market requests, breeding plans for fresh pork consumption are usually designed to reduce carcass fat content and increase lean meat deposition. However, the Italian pig industry is mainly devoted to the production of Protected Designation of Origin dry cured hams: pigs are slaughtered at around 160 kg of live weight and the breeding goal aims at maintaining fat coverage, measured as backfat thickness to avoid excessive desiccation of the hams. This objective has shaped the genetic pool of Italian heavy pig breeds for a few decades. In this study we applied a selective genotyping approach within a population of ~ 12,000 performance tested Italian Large White pigs. Within this population, we selectively genotyped 304 pigs with extreme and divergent backfat thickness estimated breeding value by the Illumina PorcineSNP60 BeadChip and performed a genome wide association study to identify loci associated to this trait. Results We identified 4 single nucleotide polymorphisms with P≤5.0E-07 and additional 119 ones with 5.0E-07 Conclusions Further investigations are needed to evaluate the effects of the identified single nucleotide polymorphisms associated with backfat thickness on other traits as a pre-requisite for practical applications in breeding programs. Reported results could improve our understanding of the biology of fat metabolism and deposition that could also be relevant for other mammalian species including humans, confirming the role of neuronal genes on obesity.

  18. IL-18 single nucleotide polymorphisms in hematologic malignancies with HLA matched sibling donor allogeneic hematopoietic stem cell transplantation

    蔡小矜

    2014-01-01

    Objective To explore the impact of interleukin-18(IL-18)single nucleotide polymorphisms on outcomes of hematologic malignancies with HLA-matched sibling donor hematopoietic stem cell transplantation(allo-HSCT).Methods Single-nucleotide polymorphisms in IL-18 promoter was detected by PCR-sequence-specific primer analysis(PCR-SSP)in 93 recipients and their HLA matched sibling donors.Hematopoietic reconstitution,

  19. Minimalist ensemble algorithms for genome-wide protein localization prediction

    Lin Jhih-Rong

    2012-07-01

    Full Text Available Abstract Background Computational prediction of protein subcellular localization can greatly help to elucidate its functions. Despite the existence of dozens of protein localization prediction algorithms, the prediction accuracy and coverage are still low. Several ensemble algorithms have been proposed to improve the prediction performance, which usually include as many as 10 or more individual localization algorithms. However, their performance is still limited by the running complexity and redundancy among individual prediction algorithms. Results This paper proposed a novel method for rational design of minimalist ensemble algorithms for practical genome-wide protein subcellular localization prediction. The algorithm is based on combining a feature selection based filter and a logistic regression classifier. Using a novel concept of contribution scores, we analyzed issues of algorithm redundancy, consensus mistakes, and algorithm complementarity in designing ensemble algorithms. We applied the proposed minimalist logistic regression (LR ensemble algorithm to two genome-wide datasets of Yeast and Human and compared its performance with current ensemble algorithms. Experimental results showed that the minimalist ensemble algorithm can achieve high prediction accuracy with only 1/3 to 1/2 of individual predictors of current ensemble algorithms, which greatly reduces computational complexity and running time. It was found that the high performance ensemble algorithms are usually composed of the predictors that together cover most of available features. Compared to the best individual predictor, our ensemble algorithm improved the prediction accuracy from AUC score of 0.558 to 0.707 for the Yeast dataset and from 0.628 to 0.646 for the Human dataset. Compared with popular weighted voting based ensemble algorithms, our classifier-based ensemble algorithms achieved much better performance without suffering from inclusion of too many individual

  20. Genome-wide sequence variations among Mycobacterium avium subspecies paratuberculosis.

    AdelMTalaat

    2011-12-01

    Full Text Available Mycobacterium avium subspecies paratuberculosis (M. ap, the causative agent of Johne’s disease (JD, infects many farmed ruminants, wildlife animals and humans. To better understand the molecular pathogenesis of these infections, we analyzed the whole genome sequences of several M. ap and M. avium subspecies avium (M. avium strains isolated from various hosts and environments. Using Next-generation sequencing technology, all 6 M. ap isolates showed a high percentage of homology (98% to the reference genome sequence of M. ap K-10 isolated from cattle. However, 2 M. avium isolates (DT 78 and Env 77 showed significant sequence diversity from the reference strain M. avium 104. The genomes of M. avium isolates DT 78 and Env 77 exhibited only 87% and 40% homology, respectively, to the M. avium 104 reference genome. Within the M. ap isolates, genomic rearrangements (insertions/deletions, Indels were not detected, and only unique single nucleotide polymorphisms (SNPs were observed among the 6 M. ap strains. While most of the SNPs (~100 in M. ap genomes were non-synonymous, a total of ~ 6000 SNPs were detected among M. avium genomes, most of them were synonymous suggesting a differential selective pressure between M. ap and M. avium isolates. In addition, SNPs-based phylo-genomic analysis showed that isolates from goat and Oryx are closely related to the cattle (K-10 strain while the human isolate (M. ap 4B is closely related to the environmental strains, indicating environmental source to human infections. Overall, SNPs were the most common variations among M. ap isolates while SNPs in addition to Indels were prevalent among M. avium isolates. Genomic variations will be useful in designing host-specific markers for the analysis of mycobacterial evolution and for developing novel diagnostics directed against Johne’s disease in animals.

  1. Genome-wide significant risk associations for mucinous ovarian carcinoma

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  2. Reducing dimensionality for prediction of genome-wide breeding values

    Woolliams John A

    2009-03-01

    Full Text Available Abstract Partial least square regression (PLSR and principal component regression (PCR are methods designed for situations where the number of predictors is larger than the number of records. The aim was to compare the accuracy of genome-wide breeding values (EBV produced using PLSR and PCR with a Bayesian method, 'BayesB'. Marker densities of 1, 2, 4 and 8 Ne markers/Morgan were evaluated when the effective population size (Ne was 100. The correlation between true breeding value and estimated breeding value increased with density from 0.611 to 0.681 and 0.604 to 0.658 using PLSR and PCR respectively, with an overall advantage to PLSR of 0.016 (s.e = 0.008. Both methods gave a lower accuracy compared to the 'BayesB', for which accuracy increased from 0.690 to 0.860. PLSR and PCR appeared less responsive to increased marker density with the advantage of 'BayesB' increasing by 17% from a marker density of 1 to 8Ne/M. PCR and PLSR showed greater bias than 'BayesB' in predicting breeding values at all densities. Although, the PLSR and PCR were computationally faster and simpler, these advantages do not outweigh the reduction in accuracy, and there is a benefit in obtaining relevant prior information from the distribution of gene effects.

  3. Genome-wide association studies in pharmacogenetics research debate

    Bailey, Kent R; Cheng, Cheng

    2016-01-01

    Will genome-wide association studies (GWAS) ‘work’ for pharmacogenetics research? This question was the topic of a staged debate, with pro and con sides, aimed to bring out the strengths and weaknesses of GWAS for pharmacogenetics studies. After a full day of seminars at the Fifth Statistical Analysis Workshop of the Pharmacogenetics Research Network, the lively debate was held – appropriately – at Goonies Comedy Club in Rochester (MN, USA). The pro side emphasized that the many GWAS successes for identifying genetic variants associated with disease risk show that it works; that the current genotyping platforms are efficient, with good imputation methods to fill in missing data; that its global assessment is always a success even if no significant associations are detected; and that genetic effects are likely to be large because humans have not evolved in a drug-therapy environment. By contrast, the con side emphasized that we have limited knowledge of the complexity of the genome; limited clinical phenotypes compromise studies; the likely multifactorial nature of drug response clouding the small genetic effects; and limitations of sample size and replication studies in pharmacogenetic studies. Lively and insightful discussions emphasized further research efforts that might benefit GWAS in pharmacogenetics. PMID:20235786

  4. Genome-wide association study of aggressive behaviour in chicken

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  5. Assessing Predictive Properties of Genome-Wide Selection in Soybeans

    Xavier, Alencar; Muir, William M.; Rainey, Katy Martin

    2016-01-01

    Many economically important traits in plant breeding have low heritability or are difficult to measure. For these traits, genomic selection has attractive features and may boost genetic gains. Our goal was to evaluate alternative scenarios to implement genomic selection for yield components in soybean (Glycine max L. merr). We used a nested association panel with cross validation to evaluate the impacts of training population size, genotyping density, and prediction model on the accuracy of genomic prediction. Our results indicate that training population size was the factor most relevant to improvement in genome-wide prediction, with greatest improvement observed in training sets up to 2000 individuals. We discuss assumptions that influence the choice of the prediction model. Although alternative models had minor impacts on prediction accuracy, the most robust prediction model was the combination of reproducing kernel Hilbert space regression and BayesB. Higher genotyping density marginally improved accuracy. Our study finds that breeding programs seeking efficient genomic selection in soybeans would best allocate resources by investing in a representative training set. PMID:27317786

  6. Genome-Wide Association Studies in Primary Biliary Cirrhosis.

    Gulamhusein, Aliya F; Juran, Brian D; Lazaridis, Konstantinos N

    2015-11-01

    Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized. PMID:26676814

  7. Genome-wide footprinting: ready for prime time?

    Sung, Myong-Hee; Baek, Songjoon; Hager, Gordon L

    2016-03-01

    High-throughput sequencing technologies have allowed many gene locus-level molecular biology assays to become genome-wide profiling methods. DNA-cleaving enzymes such as DNase I have been used to probe accessible chromatin. The accessible regions contain functional regulatory sites, including promoters, insulators and enhancers. Deep sequencing of DNase-seq libraries and computational analysis of the cut profiles have been used to infer protein occupancy in the genome at the nucleotide level, a method introduced as 'digital genomic footprinting'. The approach has been proposed as an attractive alternative to the analysis of transcription factors (TFs) by chromatin immunoprecipitation followed by sequencing (ChIP-seq), and in theory it should overcome antibody issues, poor resolution and batch effects. Recent reports point to limitations of the DNase-based genomic footprinting approach and call into question the scope of detectable protein occupancy, especially for TFs with short-lived chromatin binding. The genomics community is grappling with issues concerning the utility of genomic footprinting and is reassessing the proposed approaches in terms of robust deliverables. Here we summarize the consensus as well as different views emerging from recent reports, and we describe the remaining issues and hurdles for genomic footprinting. PMID:26914206

  8. Comparative analysis of methods for genome-wide nucleosome cartography.

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use. PMID:25296770

  9. Genome-wide discovery of small RNAs in Mycobacterium tuberculosis.

    Paolo Miotto

    Full Text Available Only few small RNAs (sRNAs have been characterized in Mycobacterium tuberculosis and their role in regulatory networks is still poorly understood. Here we report a genome-wide characterization of sRNAs in M. tuberculosis integrating experimental and computational analyses. Global RNA-seq analysis of exponentially growing cultures of M. tuberculosis H37Rv had previously identified 1373 sRNA species. In the present report we show that 258 (19% of these were also identified by microarray expression. This set included 22 intergenic sRNAs, 84 sRNAs mapping within 5'/3' UTRs, and 152 antisense sRNAs. Analysis of promoter and terminator consensus sequences identified sigma A promoter consensus sequences for 121 sRNAs (47%, terminator consensus motifs for 22 sRNAs (8.5%, and both motifs for 35 sRNAs (14%. Additionally, 20/23 candidates were visualized by Northern blot analysis and 5' end mapping by primer extension confirmed the RNA-seq data. We also used a computational approach utilizing functional enrichment to identify the pathways targeted by sRNA regulation. We found that antisense sRNAs preferentially regulated transcription of membrane-bound proteins. Genes putatively regulated by novel cis-encoded sRNAs were enriched for two-component systems and for functional pathways involved in hydrogen transport on the membrane.

  10. Genome-wide search for strabismus susceptibility loci.

    Fujiwara H

    2003-06-01

    Full Text Available The purpose of this study was to search for chromosomal susceptibility loci for comitant strabismus. Genomic DNA was isolated from 10mL blood taken from each member of 30 nuclear families in which 2 or more siblings are affected by either esotropia or exotropia. A genome-wide search was performed with amplification by polymerase chain reaction of 400 markers in microsatellite regions with approximately 10 cM resolution. For each locus, non-parametric affected sib-pair analysis and non-parametric linkage analysis for multiple pedigrees (Genehunter software, http://linkage.rockefeller.edu/soft/ were used to calculate multipoint lod scores and non-parametric linkage (NPL scores, respectively. In sib-pair analysis, lod scores showed basically flat lines with several peaks of 0.25 on all chromosomes. In non-parametric linkage analysis for multiple pedigrees, NPL scores showed one peak as high as 1.34 on chromosomes 1, 2, 4, 7, 10, 15, and 16, while 2 such peaks were found on chromosomes 3, 9, 11, 12, 18, and 20. Non-parametric linkage analysis for multiple pedigrees of 30 families with comitant strabismus suggested a number of chromosomal susceptibility loci. Our ongoing study involving a larger number of families will refine the accuracy of statistical analysis to pinpoint susceptibility loci for comitant strabismus.

  11. Genome-Wide Specific Selection in Three Domestic Sheep Breeds.

    Huihua Wang

    Full Text Available Commercial sheep raised for mutton grow faster than traditional Chinese sheep breeds. Here, we aimed to evaluate genetic selection among three different types of sheep breed: two well-known commercial mutton breeds and one indigenous Chinese breed.We first combined locus-specific branch lengths and di statistical methods to detect candidate regions targeted by selection in the three different populations. The results showed that the genetic distances reached at least medium divergence for each pairwise combination. We found these two methods were highly correlated, and identified many growth-related candidate genes undergoing artificial selection. For production traits, APOBR and FTO are associated with body mass index. For meat traits, ALDOA, STK32B and FAM190A are related to marbling. For reproduction traits, CCNB2 and SLC8A3 affect oocyte development. We also found two well-known genes, GHR (which affects meat production and quality and EDAR (associated with hair thickness were associated with German mutton merino sheep. Furthermore, four genes (POL, RPL7, MSL1 and SHISA9 were associated with pre-weaning gain in our previous genome-wide association study.Our results indicated that combine locus-specific branch lengths and di statistical approaches can reduce the searching ranges for specific selection. And we got many credible candidate genes which not only confirm the results of previous reports, but also provide a suite of novel candidate genes in defined breeds to guide hybridization breeding.

  12. Genome-Wide Discriminatory Information Patterns of Cytosine DNA Methylation

    Sanchez, Robersy; Mackenzie, Sally A.

    2016-01-01

    Cytosine DNA methylation (CDM) is a highly abundant, heritable but reversible chemical modification to the genome. Herein, a machine learning approach was applied to analyze the accumulation of epigenetic marks in methylomes of 152 ecotypes and 85 silencing mutants of Arabidopsis thaliana. In an information-thermodynamics framework, two measurements were used: (1) the amount of information gained/lost with the CDM changes IR and (2) the uncertainty of not observing a SNP LCR. We hypothesize that epigenetic marks are chromosomal footprints accounting for different ontogenetic and phylogenetic histories of individual populations. A machine learning approach is proposed to verify this hypothesis. Results support the hypothesis by the existence of discriminatory information (DI) patterns of CDM able to discriminate between individuals and between individual subpopulations. The statistical analyses revealed a strong association between the topologies of the structured population of Arabidopsis ecotypes based on IR and on LCR, respectively. A statistical-physical relationship between IR and LCR was also found. Results to date imply that the genome-wide distribution of CDM changes is not only part of the biological signal created by the methylation regulatory machinery, but ensures the stability of the DNA molecule, preserving the integrity of the genetic message under continuous stress from thermal fluctuations in the cell environment. PMID:27322251

  13. Genome-wide DNA methylation analysis in hepatocellular carcinoma.

    Yamada, Nobuhisa; Yasui, Kohichiroh; Dohi, Osamu; Gen, Yasuyuki; Tomie, Akira; Kitaichi, Tomoko; Iwai, Naoto; Mitsuyoshi, Hironori; Sumida, Yoshio; Moriguchi, Michihisa; Yamaguchi, Kanji; Nishikawa, Taichiro; Umemura, Atsushi; Naito, Yuji; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

    2016-04-01

    Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC. PMID:26883180

  14. Optical mapping discerns genome wide DNA methylation profiles

    Bergendahl Veit

    2008-07-01

    Full Text Available Abstract Background Methylation of CpG dinucleotides is a fundamental mechanism of epigenetic regulation in eukaryotic genomes. Development of methods for rapid genome wide methylation profiling will greatly facilitate both hypothesis and discovery driven research in the field of epigenetics. In this regard, a single molecule approach to methylation profiling offers several unique advantages that include elimination of chemical DNA modification steps and PCR amplification. Results A single molecule approach is presented for the discernment of methylation profiles, based on optical mapping. We report results from a series of pilot studies demonstrating the capabilities of optical mapping as a platform for methylation profiling of whole genomes. Optical mapping was used to discern the methylation profile from both an engineered and wild type Escherichia coli. Furthermore, the methylation status of selected loci within the genome of human embryonic stem cells was profiled using optical mapping. Conclusion The optical mapping platform effectively detects DNA methylation patterns. Due to single molecule detection, optical mapping offers significant advantages over other technologies. This advantage stems from obviation of DNA modification steps, such as bisulfite treatment, and the ability of the platform to assay repeat dense regions within mammalian genomes inaccessible to techniques using array-hybridization technologies.

  15. Genome-wide association study of proneness to anger.

    Eric Mick

    Full Text Available BACKGROUND: Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. METHODS: With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger State-Trait Anger Scale in the Atherosclerosis Risk in Communities (ARIC study (n = 8,747. RESULTS: Subjects were, on average, 54 (range 45-64 years old at baseline enrollment, 47% (n = 4,117 were male, and all were of European descent by self-report. The mean Angry Temperament and Angry Reaction scores were 5.8 ± 1.8 and 7.6 ± 2.2. We observed a nominally significant finding (p = 2.9E-08, λ = 1.027 - corrected pgc = 2.2E-07, λ = 1.0015 on chromosome 6q21 in the gene coding for the non-receptor protein-tyrosine kinase, Fyn. CONCLUSIONS: Fyn interacts with NDMA receptors and inositol-1,4,5-trisphosphate (IP3-gated channels to regulate calcium influx and intracellular release in the post-synaptic density. These results suggest that signaling pathways regulating intracellular calcium homeostasis, which are relevant to memory, learning, and neuronal survival, may in part underlie the expression of Angry Temperament.

  16. Genome-wide analyses of small noncoding RNAs in streptococci

    Nadja ePatenge

    2015-05-01

    Full Text Available Streptococci represent a diverse group of Gram-positive bacteria, which colonize a wide range of hosts among animals and humans. Streptococcal species occur as commensal as well as pathogenic organisms. Many of the pathogenic species can cause severe, invasive infections in their hosts leading to a high morbidity and mortality. The consequence is a tremendous suffering on the part of men and livestock besides the significant financial burden in the agricultural and healthcare sectors. An environmentally stimulated and tightly controlled expression of virulence factor genes is of fundamental importance for streptococcal pathogenicity. Bacterial small noncoding RNAs (sRNAs modulate the expression of genes involved in stress response, sugar metabolism, surface composition, and other properties that are related to bacterial virulence. Even though the regulatory character is shared by this class of RNAs, variation on the molecular level results in a high diversity of functional mechanisms. The knowledge about the role of sRNAs in streptococci is still limited, but in recent years, genome-wide screens for sRNAs have been conducted in an increasing number of species. Bioinformatics prediction approaches have been employed as well as expression analyses by classical array techniques or next generation sequencing. This review will give an overview of whole genome screens for sRNAs in streptococci with a focus on describing the different methods and comparing their outcome considering sRNA conservation among species, functional similarities, and relevance for streptococcal infection.

  17. Genome-Wide Discriminatory Information Patterns of Cytosine DNA Methylation.

    Sanchez, Robersy; Mackenzie, Sally A

    2016-01-01

    Cytosine DNA methylation (CDM) is a highly abundant, heritable but reversible chemical modification to the genome. Herein, a machine learning approach was applied to analyze the accumulation of epigenetic marks in methylomes of 152 ecotypes and 85 silencing mutants of Arabidopsis thaliana. In an information-thermodynamics framework, two measurements were used: (1) the amount of information gained/lost with the CDM changes I R and (2) the uncertainty of not observing a SNP L C R . We hypothesize that epigenetic marks are chromosomal footprints accounting for different ontogenetic and phylogenetic histories of individual populations. A machine learning approach is proposed to verify this hypothesis. Results support the hypothesis by the existence of discriminatory information (DI) patterns of CDM able to discriminate between individuals and between individual subpopulations. The statistical analyses revealed a strong association between the topologies of the structured population of Arabidopsis ecotypes based on I R and on LCR, respectively. A statistical-physical relationship between I R and L C R was also found. Results to date imply that the genome-wide distribution of CDM changes is not only part of the biological signal created by the methylation regulatory machinery, but ensures the stability of the DNA molecule, preserving the integrity of the genetic message under continuous stress from thermal fluctuations in the cell environment. PMID:27322251

  18. High density genome wide genotyping-by-sequencing and association identifies common and low frequency SNPs, and novel candidate genes influencing cow milk traits

    Ibeagha-Awemu, Eveline M.; Peters, Sunday O.; Akwanji, Kingsley A.; Imumorin, Ikhide G.; Zhao, Xin

    2016-01-01

    High-throughput sequencing technologies have increased the ability to detect sequence variations for complex trait improvement. A high throughput genome wide genotyping-by-sequencing (GBS) method was used to generate 515,787 single nucleotide polymorphisms (SNPs), from which 76,355 SNPs with call rates >85% and minor allele frequency ≥1.5% were used in genome wide association study (GWAS) of 44 milk traits in 1,246 Canadian Holstein cows. GWAS was accomplished with a mixed linear model procedure implementing the additive and dominant models. A strong signal within the centromeric region of bovine chromosome 14 was associated with test day fat percentage. Several SNPs were associated with eicosapentaenoic acid, docosapentaenoic acid, arachidonic acid, CLA:9c11t and gamma linolenic acid. Most of the significant SNPs for 44 traits studied are novel and located in intergenic regions or introns of genes. Novel potential candidate genes for milk traits or mammary gland functions include ERCC6, TONSL, NPAS2, ACER3, ITGB4, GGT6, ACOX3, MECR, ADAM12, ACHE, LRRC14, FUK, NPRL3, EVL, SLCO3A1, PSMA4, FTO, ADCK5, PP1R16A and TEP1. Our study further demonstrates the utility of the GBS approach for identifying population-specific SNPs for use in improvement of complex dairy traits. PMID:27506634

  19. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

    Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya; Hsiung, Chao A; Matsuo, Keitaro; Liu, Jie; Chen, Kexin; Yamji, Taiki; Yang, Yang; Chang, I-Shou; Wu, Chen; Hong, Yun-Chul; Burdett, Laurie; Wyatt, Kathleen; Chung, Charles C; Li, Shengchao A; Yeager, Meredith; Hutchinson, Amy; Hu, Wei; Caporaso, Neil; Landi, Maria T; Chatterjee, Nilanjan; Song, Minsun; Fraumeni, Joseph F; Kohno, Takashi; Yokota, Jun; Kunitoh, Hideo; Ashikawa, Kyota; Momozawa, Yukihide; Daigo, Yataro; Mitsudomi, Tetsuya; Yatabe, Yasushi; Hida, Toyoaki; Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Guan, Peng; Chang, Jiang; Tan, Wen; Chen, Chien-Jen; Chang, Gee-Chen; Tsai, Ying-Huang; Su, Wu-Chou; Chen, Kuan-Yu; Huang, Ming-Shyan; Chen, Yuh-Min; Zheng, Hong; Li, Haixin; Cui, Ping; Guo, Huan; Xu, Ping; Liu, Li; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Park, Jae Yong; Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa; Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu; Kim, Hee Nam; Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young; Kim, Jin Hee; Oh, In-Jae; Kim, Young-Chul; Sung, Sook Whan; Kim, Jun Suk; Yoon, Ho-Il; Kweon, Sun-Seog; Shin, Min-Ho; Seow, Adeline; Chen, Ying; Lim, Wei-Yen; Liu, Jianjun; Wong, Maria Pik; Lee, Victor Ho Fun; Bassig, Bryan A; Tucker, Margaret; Berndt, Sonja I; Chow, Wong-Ho; Ji, Bu-Tian; Wang, Junwen; Xu, Jun; Sihoe, Alan Dart Loon; Ho, James C M; Chan, John K C; Wang, Jiu-Cun; Lu, Daru; Zhao, Xueying; Zhao, Zhenhong; Wu, Junjie; Chen, Hongyan; Jin, Li; Wei, Fusheng; Wu, Guoping; An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long; Gao, Yu-Tang; Xiang, Yong-Bing; He, Xingzhou; Li, Jihua; Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Klein, Robert; Pao, William; Lawrence, Charles; Hosgood, H Dean; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Ying-Hsiang; Chen, Chung-Hsing; Wang, Wen-Chang; Chen, Chih-Yi; Wang, Chih-Liang; Yu, Chong-Jen; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Li, Yao-Jen; Yang, Tsung-Ying; Lin, Chien-Chung; Yang, Pan-Chyr; Wu, Tangchun; Lin, Dongxin; Zhou, Baosen; Yu, Jinming; Shen, Hongbing; Kubo, Michiaki; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-02-01

    Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings. PMID:26732429

  20. CDH13 and HCRTR2 May Be Associated with Hypersomnia Symptom of Bipolar Depression: A Genome-Wide Functional Enrichment Pathway Analysis.

    Cho, Chul-Hyun; Lee, Heon-Jeong; Woo, Hyun Goo; Choi, Ji-Hye; Greenwood, Tiffany A; Kelsoe, John R

    2015-07-01

    Although bipolar disorder is highly heritable, the identification of specific genetic variations is limited because of the complex traits underlying the disorder. We performed a genome-wide association study of bipolar disorder using a subphenotype that shows hypersomnia symptom during a major depressive episode. We investigated a total of 2,191 cases, 1,434 controls, and 703,012 single nucleotide polymorphisms (SNPs) in the merged samples obtained from the Translational Genomics Institute and the Genetic Association Information Network. The gene emerging as the most significant by statistical analysis was rs1553441 (odds ratio=0.4093; p=1.20×10(-5); Permuted p=6.0×10(-6)). However, the 5×0(-8) threshold for statistical significance required in a genome-wide association study was not achieved. The functional enrichment pathway analysis showed significant enrichments in the adhesion, development-related, synaptic transmission-related, and cell recognition-related pathways. For further evaluation, each gene of the enriched pathways was reviewed and matched with genes that were suggested to be associated with psychiatric disorders by previous genetic studies. We found that the cadherin 13 and hypocretin (orexin) receptor 2 genes may be involved in the hypersomnia symptom during a major depressive episode of bipolar disorder. PMID:26207136

  1. Integrative analysis of single nucleotide polymorphisms and gene expression efficiently distinguishes samples from closely related ethnic populations

    Yang Hsin-Chou

    2012-07-01

    Full Text Available Abstract Background Ancestry informative markers (AIMs are a type of genetic marker that is informative for tracing the ancestral ethnicity of individuals. Application of AIMs has gained substantial attention in population genetics, forensic sciences, and medical genetics. Single nucleotide polymorphisms (SNPs, the materials of AIMs, are useful for classifying individuals from distinct continental origins but cannot discriminate individuals with subtle genetic differences from closely related ancestral lineages. Proof-of-principle studies have shown that gene expression (GE also is a heritable human variation that exhibits differential intensity distributions among ethnic groups. GE supplies ethnic information supplemental to SNPs; this motivated us to integrate SNP and GE markers to construct AIM panels with a reduced number of required markers and provide high accuracy in ancestry inference. Few studies in the literature have considered GE in this aspect, and none have integrated SNP and GE markers to aid classification of samples from closely related ethnic populations. Results We integrated a forward variable selection procedure into flexible discriminant analysis to identify key SNP and/or GE markers with the highest cross-validation prediction accuracy. By analyzing genome-wide SNP and/or GE markers in 210 independent samples from four ethnic groups in the HapMap II Project, we found that average testing accuracies for a majority of classification analyses were quite high, except for SNP-only analyses that were performed to discern study samples containing individuals from two close Asian populations. The average testing accuracies ranged from 0.53 to 0.79 for SNP-only analyses and increased to around 0.90 when GE markers were integrated together with SNP markers for the classification of samples from closely related Asian populations. Compared to GE-only analyses, integrative analyses of SNP and GE markers showed comparable testing

  2. Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways

    Cristina L. Ronchi

    2012-03-01

    Full Text Available The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0 to detect copy number alterations (CNAs and copy-neutral losses of heterozygosity (cnLOH in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≥20% of cases, most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses, including genes involved in steroidogenesis (CYP11B1 or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT. Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.

  3. Genetic analysis of the cardiac methylome at single nucleotide resolution in a model of human cardiovascular disease.

    Michelle D Johnson

    2014-12-01

    Full Text Available Epigenetic marks such as cytosine methylation are important determinants of cellular and whole-body phenotypes. However, the extent of, and reasons for inter-individual differences in cytosine methylation, and their association with phenotypic variation are poorly characterised. Here we present the first genome-wide study of cytosine methylation at single-nucleotide resolution in an animal model of human disease. We used whole-genome bisulfite sequencing in the spontaneously hypertensive rat (SHR, a model of cardiovascular disease, and the Brown Norway (BN control strain, to define the genetic architecture of cytosine methylation in the mammalian heart and to test for association between methylation and pathophysiological phenotypes. Analysis of 10.6 million CpG dinucleotides identified 77,088 CpGs that were differentially methylated between the strains. In F1 hybrids we found 38,152 CpGs showing allele-specific methylation and 145 regions with parent-of-origin effects on methylation. Cis-linkage explained almost 60% of inter-strain variation in methylation at a subset of loci tested for linkage in a panel of recombinant inbred (RI strains. Methylation analysis in isolated cardiomyocytes showed that in the majority of cases methylation differences in cardiomyocytes and non-cardiomyocytes were strain-dependent, confirming a strong genetic component for cytosine methylation. We observed preferential nucleotide usage associated with increased and decreased methylation that is remarkably conserved across species, suggesting a common mechanism for germline control of inter-individual variation in CpG methylation. In the RI strain panel, we found significant correlation of CpG methylation and levels of serum chromogranin B (CgB, a proposed biomarker of heart failure, which is evidence for a link between germline DNA sequence variation, CpG methylation differences and pathophysiological phenotypes in the SHR strain. Together, these results will

  4. Mining of haplotype-based expressed sequence tag single nucleotide polymorphisms in citrus

    Chen, Chunxian; Gmitter Jr, Fred G

    2013-01-01

    Background Single nucleotide polymorphisms (SNPs), the most abundant variations in a genome, have been widely used in various studies. Detection and characterization of citrus haplotype-based expressed sequence tag (EST) SNPs will greatly facilitate further utilization of these gene-based resources. Results In this paper, haplotype-based SNPs were mined out of publicly available citrus expressed sequence tags (ESTs) from different citrus cultivars (genotypes) individually and collectively for...

  5. Candidate Single Nucleotide Polymorphism Markers for Arsenic Responsiveness of Protein Targets

    Graham-Evans, Barbara E.; Udensi, Udensi K.; Tchounwou, Paul B.; Rajendram V. Rajnarayanan; Anyanwu, Matthew N; Cohly, Hari H.P.; Isokpehi, Raphael D.

    2010-01-01

    Arsenic is a toxic metalloid that causes skin cancer and binds to cysteine residues—a property that could be used to infer arsenic responsiveness of a target protein. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) result in amino acid substitutions and may alter arsenic binding with cysteine residues. Thus, the objective of this investigation was to identify and analyze nsSNPs that lead to substitutions to or from cysteine residues as an indication of increased or decreased arsenic r...

  6. Development of 101 Gene-based Single Nucleotide Polymorphism Markers in Sea Cucumber, Apostichopus japonicus

    Wei Lu; Shi Wang; Xiaoyu Mu; Meilin Tian; Huixia Du; Zhenmin Bao; Jingjing Yan

    2012-01-01

    Single nucleotide polymorphisms (SNPs) are currently the marker of choice in a variety of genetic studies. Using the high resolution melting (HRM) genotyping approach, 101 gene-based SNP markers were developed for Apostichopus japonicus, a sea cucumber species with economic significance for the aquaculture industry in East Asian countries. HRM analysis revealed that all the loci showed polymorphisms when evaluated using 40 A. japonicus individuals col...

  7. Jitterbug: somatic and germline transposon insertion detection at single-nucleotide resolution

    H??naff, Elizabeth; Zapata Ortiz, Luis; Casacuberta, Josep M.; Ossowski, Stephan

    2015-01-01

    Background Transposable elements are major players in genome evolution. Transposon insertion polymorphisms can translate into phenotypic differences in plants and animals and are linked to different diseases including human cancer, making their characterization highly relevant to the study of genome evolution and genetic diseases. Results Here we present Jitterbug, a novel tool that identifies transposable element insertion sites at single-nucleotide resolution based on the pairedend mapping ...

  8. Facile method for automated genotyping of single nucleotide polymorphisms by mass spectrometry

    Sauer, Sascha; Gelfand, David H.; Boussicault, Francis; Bauer, Keith; Reichert, Fred; Gut, Ivo G.

    2002-01-01

    In the future, analysis of single nucleotide polymorphisms (SNPs) should become a powerful tool for many genetic applications in areas such as association studies, pharmacogenetics and traceability in the agro-alimentary sector. A number of technologies have been developed for high-throughput genotyping of SNPs. Here we present the simplified GOOD assay for SNP genotyping by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI). The simplified GOOD assay is a si...

  9. Paclitaxel sensitivity in relation to ABCB1 expression, efflux and single nucleotide polymorphisms in ovarian cancer

    Gao, Bo; Russell, Amanda; Beesley, Jonathan; Chen, Xiao Qing; Healey, Sue; Henderson, Michelle; Wong, Mark; Emmanuel, Catherine; Johnatty, Sharon E.; ,; Bowtell, David; Gertig, Dorota; Green, Adle; Webb, Penelope; Hung, Jillian

    2014-01-01

    ABCB1 (adenosine triphosphate-binding cassette transporter B1) mediates cellular elimination of many chemotherapeutic agents including paclitaxel, which is commonly used to treat ovarian cancer. A significant association between common single nucleotide polymorphisms (SNPs) in ABCB1 and progression-free survival has been reported in patients with ovarian cancer. Variable paclitaxel clearance due to genotype specific differences in ABCB1 activity in cancer cells and/or normal tissues may under...

  10. Single-Nucleotide Polymorphisms and Markers of Oxidative Stress in Healthy Women

    Minlikeeva, Albina N.; Browne, Richard W.; Ochs-Balcom, Heather M.; Catalin Marian; Shields, Peter G.; Maurizio Trevisan; Shiva Krishnan; Ramakrishna Modali; Michael Seddon; Teresa Lehman; Freudenheim, Jo L.

    2016-01-01

    Purpose There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress. Methods We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white...

  11. Identifying association model for single-nucleotide polymorphisms of ORAI1 gene for breast cancer

    Chang, Wei-Chiao; Fang, Yong-Yuan; Chang, Hsueh-Wei; Chuang, Li-Yeh; Lin, Yu-Da; Hou, Ming-Feng; Yang, Cheng-Hong

    2014-01-01

    Background ORAI1 channels play an important role for breast cancer progression and metastasis. Previous studies indicated the strong correlation between breast cancer and individual single nucleotide polymorphisms (SNPs) of ORAI1 gene. However, the possible SNP-SNP interaction of ORAI1 gene was not investigated. Results To develop the complex analyses of SNP-SNP interaction, we propose a genetic algorithm (GA) to detect the model of breast cancer association between five SNPs (rs12320939, rs1...

  12. Evaluation of 13q14 Status in Multiple Myeloma by Digital Single Nucleotide Polymorphism Technology

    Hanlon, Katy; Harries, Lorna W.; Ellard, Sian; Rudin, Claudius E.

    2009-01-01

    Chromosome 13q deletions are common in multiple myeloma and other cancers, demonstrating the importance of this region in tumorigenesis. We used a novel single nucleotide polymorphism (SNP)-based technique, digital SNP (dSNP), to identify loss of heterozygosity (LOH) at chromosome 13q in paraffin-embedded bone marrow biopsies from 22 patients with multiple myeloma. We analyzed heterozygous SNPs at 13q for the presence of allelic imbalances and examined the results by sequential probability ra...

  13. SNP@Promoter: a database of human SNPs (Single Nucleotide Polymorphisms) within the putative promoter regions

    Chung Won-Hyong; Park Daeui; Kim Woo-Yeon; Kim Byoung-Chul; Shin Kwang-sik; Bhak Jong

    2008-01-01

    Abstract Background Analysis of single nucleotide polymorphism (SNP) is becoming a key research in genomics fields. Many functional analyses of SNPs have been carried out for coding regions and splicing sites that can alter proteins and mRNA splicing. However, SNPs in non-coding regulatory regions can also influence important biological regulation. Presently, there are few databases for SNPs in non-coding regulatory regions. Description We identified 488,452 human SNPs in the putative promote...

  14. Single nucleotide polymorphisms in the bovine Histophilus somni genome; a comparison of new and old isolates

    Madampage, Claudia Avis; Rawlyk, Neil; Crockford, Gordon; Van Donkersgoed, Joyce; Dorin, Craig; Potter, Andrew

    2015-01-01

    Histophilus somni, a causative agent of the bovine respiratory disease complex, can also cause a variety of systemic disorders, including bronchopneumonia, myocarditis, pericarditis, arthritis, pleuritis, and infectious thrombotic meningoencephalitis. The purpose of this study was to determine if currently circulating strains differ from those of the 1980s by identifying genomic changes. Single nucleotide polymorphisms (SNPs) and insertion and deletion (INDEL) sites were examined by whole-gen...

  15. Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies

    Miao-Xin Li; Kwan, Johnny S.H.; Su-Ying Bao; Wanling Yang; Shu-Leong Ho; Yong-Qiang Song; Sham, Pak C

    2013-01-01

    Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiase...

  16. Assessing patterns of hybridization between North Atlantic eels using diagnostic single-nucleotide polymorphisms

    Pujolar, M; Jacobsen, W; Als, D; Frydenberg, J.; Magnussen, E.; Jonsson, B.; Jiang, X.; L. Cheng; Bekkevold, D; Maes, G.E.; Bernatchez, L.; Hansen, M.

    2014-01-01

    The two North Atlantic eel species, the European eel (Anguilla anguilla) and the American eel (Anguilla rostrata), spawn in partial sympatry in the Sargasso Sea, providing ample opportunity to interbreed. In this study, we used a RAD (Restriction site Associated DNA) sequencing approach to identify species-specific diagnostic single-nucleotide polymorphisms (SNPs) and design a low-density array that combined with screening of a diagnostic mitochondrial DNA marker. Eels from Iceland (N =159) a...

  17. A High-Density Single Nucleotide Polymorphism Map for Neurospora crassa

    Lambreghts, Randy; Shi, Mi; Belden, William J.; DeCaprio, David; Park, Danny; Henn, Matthew R.; Galagan, James E; Baştürkmen, Meray; Birren, Bruce W.; Sachs, Matthew S.; Dunlap, Jay C.; Loros, Jennifer J.

    2009-01-01

    We report the discovery and validation of a set of single nucleotide polymorphisms (SNPs) between the reference Neurospora crassa strain Oak Ridge and the Mauriceville strain (FGSC 2555), of sufficient density to allow fine mapping of most loci. Sequencing of Mauriceville cDNAs and alignment to the completed genomic sequence of the Oak Ridge strain identified 19,087 putative SNPs. Of these, a subset was validated by cleaved amplified polymorphic sequence (CAPS), a simple and robust PCR-based ...

  18. High-throughput single nucleotide polymorphism genotyping using nanofluidic Dynamic Arrays

    Crenshaw Andrew; Hutchinson Amy; Hicks Belynda; Yeager Meredith; Berndt Sonja; Huang Wen-Yi; Hayes Richard; Chanock Stephen; Wang Jun; Lin Min; Jones Robert; Ramakrishnan Ramesh

    2009-01-01

    Abstract Background Single nucleotide polymorphisms (SNPs) have emerged as the genetic marker of choice for mapping disease loci and candidate gene association studies, because of their high density and relatively even distribution in the human genomes. There is a need for systems allowing medium multiplexing (ten to hundreds of SNPs) with high throughput, which can efficiently and cost-effectively generate genotypes for a very large sample set (thousands of individuals). Methods that are fle...

  19. Protected DNA strand displacement for enhanced single nucleotide discrimination in double-stranded DNA

    Khodakov, Dmitriy A.; Khodakova, Anastasia S.; Huang, David M.; Adrian Linacre; Ellis, Amanda V.

    2015-01-01

    Single nucleotide polymorphisms (SNPs) are a prime source of genetic diversity. Discriminating between different SNPs provides an enormous leap towards the better understanding of the uniqueness of biological systems. Here we report on a new approach for SNP discrimination using toehold-mediated DNA strand displacement. The distinctiveness of the approach is based on the combination of both 3- and 4-way branch migration mechanisms, which allows for reliable discrimination of SNPs within doubl...

  20. Development of a single nucleotide polymorphism barcode to genotype Plasmodium vivax infections.

    Mary Lynn Baniecki; Aubrey L Faust; Schaffner, Stephen F.; Park, Daniel J.; Kevin Galinsky; Daniels, Rachel F; Elizabeth Hamilton; Ferreira, Marcelo U.; Karunaweera, Nadira D.; David Serre; Zimmerman, Peter A.; Sá, Juliana M; Wellems, Thomas E.; Lise Musset; Eric Legrand

    2015-01-01

    Plasmodium vivax, one of the five species of Plasmodium parasites that cause human malaria, is responsible for 25-40% of malaria cases worldwide. Malaria global elimination efforts will benefit from accurate and effective genotyping tools that will provide insight into the population genetics and diversity of this parasite. The recent sequencing of P. vivax isolates from South America, Africa, and Asia presents a new opportunity by uncovering thousands of novel single nucleotide polymorphisms...

  1. Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing

    Tejedor Vaquero, Juan Ram??n, 1984-; Tilgner, Hagen; Iannone, Camilla; Guig?? Serra, Roderic; Valc??rcel, J. (Juan)

    2015-01-01

    The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correl...

  2. Endothelial Nitric Oxide Synthase Single Nucleotide Polymorphism and Left Ventricular Function in Early Chronic Kidney Disease

    Sourabh Chand; Colin D Chue; Edwards, Nicola C.; James Hodson; Simmonds, Matthew J.; Alexander Hamilton; Gough, Stephen C L; Lorraine Harper; Steeds, Rick P.; Townend, Jonathan N.; Ferro, Charles J.; Richard Borrows

    2015-01-01

    Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investi...

  3. A single nucleotide polymorphism in EZH2 predicts overall survival rate in patients with cholangiocarcinoma

    Paolicchi, Elisa; PACETTI, PAOLA; Giovannetti, Elisa; MAMBRINI, ANDREA; ORLANDI, MASSIMO; Crea, Francesco; Romani, Antonello A.; TARTARINI, ROBERTA; DANESI, ROMANO; Peters, Godefridus J; Cantore, Maurizio

    2013-01-01

    Cholangiocarcinoma (CCA) is a deadly disease arising from the malignant transformation of cholangiocytes. Enhancer of zeste homolog 2 (EZH2) is overexpressed in poorly differentiated CCA. Functional single nucleotide polymorphisms (SNPs) in this gene may affect the role of EZH2 in cholangiocarcinogenesis and chemoresistance. The aim of the current study was to evaluate the correlation between EZH2 SNPs and clinical outcome. Using PROMO3.0, GeneCard and MicroSNiper, 4 EZH2 SNPs with functional...

  4. Association of a single nucleotide polymorphism in titin gene with marbling in Japanese Black beef cattle

    Yamada, Takahisa; Sasaki, Seiki; Sukegawa, Shin; Yoshioka, Sachiyo; Takahagi, Youichi; MORITA, Mitsuo; Murakami, Hiroshi; Morimatsu, Fumiki; Fujita, Tatsuo; Miyake, Takeshi; Sasaki, Yoshiyuki

    2009-01-01

    Background: Marbling defined by the amount and distribution of intramuscular fat is an economically important trait of beef cattle in Japan. We have recently reported that single nucleotide polymorphisms (SNPs) in the endothelial differentiation, sphingolipid G-protein-coupled receptor, 1 (EDG1) gene were associated with marbling in Japanese Black beef cattle. As well as EDG1, the titin (TTN) gene, involved in myofibrillogenesis, has been previously shown to possess expression difference in m...

  5. Association of a single nucleotide polymorphism in titin gene with marbling in Japanese Black beef cattle

    Fujita Tatsuo; Morimatsu Fumiki; Murakami Hiroshi; Morita Mitsuo; Takahagi Youichi; Yoshioka Sachiyo; Sukegawa Shin; Sasaki Seiki; Yamada Takahisa; Miyake Takeshi; Sasaki Yoshiyuki

    2009-01-01

    Abstract Background Marbling defined by the amount and distribution of intramuscular fat is an economically important trait of beef cattle in Japan. We have recently reported that single nucleotide polymorphisms (SNPs) in the endothelial differentiation, sphingolipid G-protein-coupled receptor, 1 (EDG1) gene were associated with marbling in Japanese Black beef cattle. As well as EDG1, the titin (TTN) gene, involved in myofibrillogenesis, has been previously shown to possess expression differe...

  6. Nanoparticle-based detection and quantification of DNA with single nucleotide polymorphism (SNP) discrimination selectivity

    Qin, Wei Jie; Yung, Lin Yue Lanry

    2007-01-01

    Sequence-specific DNA detection is important in various biomedical applications such as gene expression profiling, disease diagnosis and treatment, drug discovery and forensic analysis. Here we report a gold nanoparticle-based method that allows DNA detection and quantification and is capable of single nucleotide polymorphism (SNP) discrimination. The precise quantification of single-stranded DNA is due to the formation of defined nanoparticle-DNA conjugate groupings in the presence of target...

  7. Association of Nitric Oxide Synthase and Matrix Metalloprotease Single Nucleotide Polymorphisms with Preeclampsia and Its Complications

    Leonardo, Daniela P.; Albuquerque, Dulcinéia M.; Lanaro, Carolina; Baptista, Letícia C.; Cecatti, José G.; Surita, Fernanda G.; Parpinelli, Mary A.; Costa, Fernando F.; Franco-Penteado, Carla F.; Fertrin, Kleber Y.; Costa, Maria Laura

    2015-01-01

    Background Preeclampsia is one of the leading causes of maternal and neonatal morbidity and mortality in the world, but its appearance is still unpredictable and its pathophysiology has not been entirely elucidated. Genetic studies have associated single nucleotide polymorphisms in genes encoding nitric oxide synthase and matrix metalloproteases with preeclampsia, but the results are largely inconclusive across different populations. Objectives To investigate the association of single nucleotide polymorphisms (SNPs) in NOS3 (G894T, T-786C, and a variable number of tandem repetitions VNTR in intron 4), MMP2 (C-1306T), and MMP9 (C-1562T) genes with preeclampsia in patients from Southeastern Brazil. Methods This prospective case-control study enrolled 77 women with preeclampsia and 266 control pregnant women. Clinical data were collected to assess risk factors and the presence of severe complications, such as eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Results We found a significant association between the single nucleotide polymorphism NOS3 T-786C and preeclampsia, independently from age, height, weight, or the other SNPs studied, and no association was found with the other polymorphisms. Age and history of preeclampsia were also identified as risk factors. The presence of at least one polymorphic allele for NOS3 T-786C was also associated with the occurrence of eclampsia or HELLP syndrome among preeclamptic women. Conclusions Our data support that the NOS3 T-786C SNP is associated with preeclampsia and the severity of its complications. PMID:26317342

  8. Association of Nitric Oxide Synthase and Matrix Metalloprotease Single Nucleotide Polymorphisms with Preeclampsia and Its Complications.

    Daniela P Leonardo

    Full Text Available Preeclampsia is one of the leading causes of maternal and neonatal morbidity and mortality in the world, but its appearance is still unpredictable and its pathophysiology has not been entirely elucidated. Genetic studies have associated single nucleotide polymorphisms in genes encoding nitric oxide synthase and matrix metalloproteases with preeclampsia, but the results are largely inconclusive across different populations.To investigate the association of single nucleotide polymorphisms (SNPs in NOS3 (G894T, T-786C, and a variable number of tandem repetitions VNTR in intron 4, MMP2 (C-1306T, and MMP9 (C-1562T genes with preeclampsia in patients from Southeastern Brazil.This prospective case-control study enrolled 77 women with preeclampsia and 266 control pregnant women. Clinical data were collected to assess risk factors and the presence of severe complications, such as eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets syndrome.We found a significant association between the single nucleotide polymorphism NOS3 T-786C and preeclampsia, independently from age, height, weight, or the other SNPs studied, and no association was found with the other polymorphisms. Age and history of preeclampsia were also identified as risk factors. The presence of at least one polymorphic allele for NOS3 T-786C was also associated with the occurrence of eclampsia or HELLP syndrome among preeclamptic women.Our data support that the NOS3 T-786C SNP is associated with preeclampsia and the severity of its complications.

  9. Approach to analysis of single nucleotide polymorphisms by automated constant denaturant capillary electrophoresis

    Melting gel techniques have proven to be amenable and powerful tools in point mutation and single nucleotide polymorphism (SNP) analysis. With the introduction of commercially available capillary electrophoresis instruments, a partly automated platform for denaturant capillary electrophoresis with potential for routine screening of selected target sequences has been established. The aim of this article is to demonstrate the use of automated constant denaturant capillary electrophoresis (ACDCE) in single nucleotide polymorphism analysis of various target sequences. Optimal analysis conditions for different single nucleotide polymorphisms on ACDCE are evaluated with the Poland algorithm. Laboratory procedures include only PCR and electrophoresis. For direct genotyping of individual SNPs, the samples are analyzed with an internal standard and the alleles are identified by co-migration of sample and standard peaks. In conclusion, SNPs suitable for melting gel analysis based on theoretical thermodynamics were separated by ACDCE under appropriate conditions. With this instrumentation (ABI 310 Genetic Analyzer), 48 samples could be analyzed without any intervention. Several institutions have capillary instrumentation in-house, thus making this SNP analysis method accessible to large groups of researchers without any need for instrument modification

  10. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose.

    Fumihiko Takeuchi

    2009-03-01

    Full Text Available We report the first genome-wide association study (GWAS whose sample size (1,053 Swedish subjects is sufficiently powered to detect genome-wide significance (p<1.5 x 10(-7 for polymorphisms that modestly alter therapeutic warfarin dose. The anticoagulant drug warfarin is widely prescribed for reducing the risk of stroke, thrombosis, pulmonary embolism, and coronary malfunction. However, Caucasians vary widely (20-fold in the dose needed for therapeutic anticoagulation, and hence prescribed doses may be too low (risking serious illness or too high (risking severe bleeding. Prior work established that approximately 30% of the dose variance is explained by single nucleotide polymorphisms (SNPs in the warfarin drug target VKORC1 and another approximately 12% by two non-synonymous SNPs (*2, *3 in the cytochrome P450 warfarin-metabolizing gene CYP2C9. We initially tested each of 325,997 GWAS SNPs for association with warfarin dose by univariate regression and found the strongest statistical signals (p<10(-78 at SNPs clustering near VKORC1 and the second lowest p-values (p<10(-31 emanating from CYP2C9. No other SNPs approached genome-wide significance. To enhance detection of weaker effects, we conducted multiple regression adjusting for known influences on warfarin dose (VKORC1, CYP2C9, age, gender and identified a single SNP (rs2108622 with genome-wide significance (p = 8.3 x 10(-10 that alters protein coding of the CYP4F2 gene. We confirmed this result in 588 additional Swedish patients (p<0.0029 and, during our investigation, a second group provided independent confirmation from a scan of warfarin-metabolizing genes. We also thoroughly investigated copy number variations, haplotypes, and imputed SNPs, but found no additional highly significant warfarin associations. We present power analysis of our GWAS that is generalizable to other studies, and conclude we had 80% power to detect genome-wide significance for common causative variants or markers

  11. A genome-wide linkage and association study using COGA data

    Cao Guichan; Kan Donghui; Cooper Richard; Zhu Xiaofeng; Wu Xiaodong

    2005-01-01

    Abstract Background Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. Methods Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using singl...

  12. A genome-wide linkage and association study using COGA data

    Zhu, Xiaofeng; Cooper, Richard; Kan, Donghui; Cao, Guichan; Wu, Xiaodong

    2005-01-01

    Background Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. Methods Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleot...

  13. Meta-Analysis in Genome-Wide Association Datasets: Strategies and Application in Parkinson Disease

    Evangelou, Evangelos; Maraganore, Demetrius M.; Ioannidis, John P. A.

    2007-01-01

    Background Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. Methodology/Principal Findings Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we...

  14. Association of a single nucleotide polymorphism at 6q25.1,rs2046210, with endometrial cancer risk among Chinese women

    Guoliang Li; Qiuyin Cai; Yong-Bing Xiang; Regina Courtney; Jia-Rong Cheng; Bo Huang; Ji-Rong Long; Hui Cai; Wei Zheng; Xiao-Ou Shu

    2011-01-01

    A recent genome-wide association study identified a new susceptibility locus for breast cancer, rs2046210, which is a single nucleotide polymorphism (SNP) located upstream of the estrogen receptor α (ESR1) gene on chromosome 6q25.1. Given that endometrial cancer shares many risk factors with breast cancer and both are related to estrogen exposure and that rs2046210 is in close proximity to the ESR1 gene, we evaluated the association of SNP rs2046210 with endometrial cancer risk among 953 cases and 947 controls in a population-based, case-control study conducted in Shanghai, China. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (95% Cis) after adjusting for potential confounders. We found that the A allele of rs2046210, linked to an increased risk of breast cancer, was associated with increased but not statistically significant risk of endometrial cancer (OR = 1.16, 95% CI = 0.96-1.41 for the GA and AA genotypes compared with the GG genotype); the association was stronger among post-menopausal women (OR = 1.28, 95% CI = 1.00-1.65). The association tended to be stronger among women with higher or longer estrogen exposure than among women with relatively lower or shorter exposure to estrogen. Our study suggests that rs2046210 may play a role in the etiology of endometrial cancer. Additional studies are needed to confirm our findings.

  15. Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants.

    Yang, Li; Neale, Benjamin M; Liu, Lu; Lee, S Hong; Wray, Naomi R; Ji, Ning; Li, Haimei; Qian, Qiujin; Wang, Dongliang; Li, Jun; Faraone, Stephen V; Wang, Yufeng; Doyle, Alysa E; Reif, Andreas; Rothenberger, Aribert; Franke, Barbara; Sonuga-Barke, Edmund J S; Steinhausen, Hans-Christoph; Buitelaar, Jan K; Kuntsi, Jonna; Biederman, Joseph; Lesch, Klaus-Peter; Kent, Lindsey; Asherson, Philip; Oades, Robert D; Loo, Sandra K; Nelson, Stan F; Faraone, Stephen V; Smalley, Susan L; Banaschewski, Tobias; Arias Vasquez, Alejandro; Todorov, Alexandre; Charach, Alice; Miranda, Ana; Warnke, Andreas; Thapar, Anita; Neale, Benjamin M; Cormand, Bru; Freitag, Christine; Mick, Eric; Mulas, Fernando; Middleton, Frank; HakonarsonHakonarson, Hakon; Palmason, Haukur; Schäfer, Helmut; Roeyers, Herbert; McGough, James J; Romanos, Jasmin; Crosbie, Jennifer; Meyer, Jobst; Ramos-Quiroga, Josep Antoni; Sergeant, Joseph; Elia, Josephine; Langely, Kate; Nisenbaum, Laura; Romanos, Marcel; Daly, Mark J; Ribasés, Marta; Gill, Michael; O'Donovan, Michael; Owen, Michael; Casas, Miguel; Bayés, Mònica; Lambregts-Rommelse, Nanda; Williams, Nigel; Holmans, Peter; Anney, Richard J L; Ebstein, Richard P; Schachar, Russell; Medland, Sarah E; Ripke, Stephan; Walitza, Susanne; Nguyen, Thuy Trang; Renner, Tobias J; Hu, Xiaolan

    2013-07-01

    Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. PMID:23728934

  16. Combination of microRNA expression profiling with genome-wide SNP genotyping to construct a coronary artery disease-related miRNA-miRNA synergistic network.

    Hua, Lin; Xia, Hong; Zhou, Ping; Li, Dongguo; Li, Lin

    2014-12-01

    In recent years, microRNAs (miRNAs) were found to play critical roles in many important biological processes. On the other hand, the rapid development of genome-wide association studies (GWAS) help identify potential genetic variants associated with the disease phenotypic variance. Therefore, we suggested a combined analysis of microRNA expression profiling with genome-wide Single Nucleotide Polymorphism (SNP) genotyping to identify potential disease-related biomarkers. Considering functional SNPs in miRNA genes or target sites might be important signals associated with human complex diseases, we constructed a miRNA-miRNA synergistic network related to coronary artery disease (CAD) by performing a genome-wide scan for SNPs in human miRNA 3' -untranslated regions (UTRs) target sites and computed potential SNP cooperation effects contributing to disease based on potential miRNA-SNP interactions reported recently. Furthermore, we identified some potential CAD-related miRNAs by analyzing the constructed miRNAmiRNA synergistic network. As a result, the predicted miRNA-miRNA network and miRNA clusters were validated by significantly high interaction effects of CAD-related miRNAs. Accurate classification performances were obtained for all of the identified miRNA clusters, and the sensitivity and specificity were all more than 90%. The network topological analysis confirmed some novel CAD-related miRNAs identified recently by experiments. Our method might help to understand miRNA function and CAD disease, as well as to explore the novel mechanisms involved. PMID:25641175

  17. Probabilistic protein function prediction from heterogeneous genome-wide data.

    Naoki Nariai

    Full Text Available Dramatic improvements in high throughput sequencing technologies have led to a staggering growth in the number of predicted genes. However, a large fraction of these newly discovered genes do not have a functional assignment. Fortunately, a variety of novel high-throughput genome-wide functional screening technologies provide important clues that shed light on gene function. The integration of heterogeneous data to predict protein function has been shown to improve the accuracy of automated gene annotation systems. In this paper, we propose and evaluate a probabilistic approach for protein function prediction that integrates protein-protein interaction (PPI data, gene expression data, protein motif information, mutant phenotype data, and protein localization data. First, functional linkage graphs are constructed from PPI data and gene expression data, in which an edge between nodes (proteins represents evidence for functional similarity. The assumption here is that graph neighbors are more likely to share protein function, compared to proteins that are not neighbors. The functional linkage graph model is then used in concert with protein domain, mutant phenotype and protein localization data to produce a functional prediction. Our method is applied to the functional prediction of Saccharomyces cerevisiae genes, using Gene Ontology (GO terms as the basis of our annotation. In a cross validation study we show that the integrated model increases recall by 18%, compared to using PPI data alone at the 50% precision. We also show that the integrated predictor is significantly better than each individual predictor. However, the observed improvement vs. PPI depends on both the new source of data and the functional category to be predicted. Surprisingly, in some contexts integration hurts overall prediction accuracy. Lastly, we provide a comprehensive assignment of putative GO terms to 463 proteins that currently have no assigned function.

  18. Genephony: a knowledge management tool for genome-wide research

    Riva Alberto

    2009-09-01

    Full Text Available Abstract Background One of the consequences of the rapid and widespread adoption of high-throughput experimental technologies is an exponential increase of the amount of data produced by genome-wide experiments. Researchers increasingly need to handle very large volumes of heterogeneous data, including both the data generated by their own experiments and the data retrieved from publicly available repositories of genomic knowledge. Integration, exploration, manipulation and interpretation of data and information therefore need to become as automated as possible, since their scale and breadth are, in general, beyond the limits of what individual researchers and the basic data management tools in normal use can handle. This paper describes Genephony, a tool we are developing to address these challenges. Results We describe how Genephony can be used to manage large datesets of genomic information, integrating them with existing knowledge repositories. We illustrate its functionalities with an example of a complex annotation task, in which a set of SNPs coming from a genotyping experiment is annotated with genes known to be associated to a phenotype of interest. We show how, thanks to the modular architecture of Genephony and its user-friendly interface, this task can be performed in a few simple steps. Conclusion Genephony is an online tool for the manipulation of large datasets of genomic information. It can be used as a browser for genomic data, as a high-throughput annotation tool, and as a knowledge discovery tool. It is designed to be easy to use, flexible and extensible. Its knowledge management engine provides fine-grained control over individual data elements, as well as efficient operations on large datasets.

  19. Genome-wide survey for biologically functional pseudogenes.

    Orjan Svensson

    2006-05-01

    Full Text Available According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human-mouse species split, and also a larger group of primate-specific ones found from human-chimpanzee searches. Two processed sequences are notable, their conservation since the human-mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3, and one from the Spinocerebellar ataxia type 1 protein (ATX1. Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios.

  20. Genome-wide survey for biologically functional pseudogenes.

    Svensson, Orjan; Arvestad, Lars; Lagergren, Jens

    2006-05-01

    According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human-mouse species split, and also a larger group of primate-specific ones found from human-chimpanzee searches. Two processed sequences are notable, their conservation since the human-mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios. PMID:16680195

  1. Identification of neural outgrowth genes using genome-wide RNAi.

    Katharine J Sepp

    2008-07-01

    Full Text Available While genetic screens have identified many genes essential for neurite outgrowth, they have been limited in their ability to identify neural genes that also have earlier critical roles in the gastrula, or neural genes for which maternally contributed RNA compensates for gene mutations in the zygote. To address this, we developed methods to screen the Drosophila genome using RNA-interference (RNAi on primary neural cells and present the results of the first full-genome RNAi screen in neurons. We used live-cell imaging and quantitative image analysis to characterize the morphological phenotypes of fluorescently labelled primary neurons and glia in response to RNAi-mediated gene knockdown. From the full genome screen, we focused our analysis on 104 evolutionarily conserved genes that when downregulated by RNAi, have morphological defects such as reduced axon extension, excessive branching, loss of fasciculation, and blebbing. To assist in the phenotypic analysis of the large data sets, we generated image analysis algorithms that could assess the statistical significance of the mutant phenotypes. The algorithms were essential for the analysis of the thousands of images generated by the screening process and will become a valuable tool for future genome-wide screens in primary neurons. Our analysis revealed unexpected, essential roles in neurite outgrowth for genes representing a wide range of functional categories including signalling molecules, enzymes, channels, receptors, and cytoskeletal proteins. We also found that genes known to be involved in protein and vesicle trafficking showed similar RNAi phenotypes. We confirmed phenotypes of the protein trafficking genes Sec61alpha and Ran GTPase using Drosophila embryo and mouse embryonic cerebral cortical neurons, respectively. Collectively, our results showed that RNAi phenotypes in primary neural culture can parallel in vivo phenotypes, and the screening technique can be used to identify many new

  2. Genome-wide characteristics of de novo mutations in autism

    Yuen, Ryan K C; Merico, Daniele; Cao, Hongzhi; Pellecchia, Giovanna; Alipanahi, Babak; Thiruvahindrapuram, Bhooma; Tong, Xin; Sun, Yuhui; Cao, Dandan; Zhang, Tao; Wu, Xueli; Jin, Xin; Zhou, Ze; Liu, Xiaomin; Nalpathamkalam, Thomas; Walker, Susan; Howe, Jennifer L.; Wang, Zhuozhi; MacDonald, Jeffrey R.; Chan, Ada; D’Abate, Lia; Deneault, Eric; Siu, Michelle T.; Tammimies, Kristiina; Uddin, Mohammed; Zarrei, Mehdi; Wang, Mingbang; Li, Yingrui; Wang, Jun; Wang, Jian; Yang, Huanming; Bookman, Matt; Bingham, Jonathan; Gross, Samuel S.; Loy, Dion; Pletcher, Mathew; Marshall, Christian R.; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Weksberg, Rosanna; Fernandez, Bridget A; Roberts, Wendy; Szatmari, Peter; Glazer, David; Frey, Brendan J.; Ring, Robert H.; Xu, Xun; Scherer, Stephen W.

    2016-01-01

    De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10−10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10−13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10−24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10−9; OR=1.84), of which 15.6% (p=4.3×10−3) and 22.5% (p=7.0×10−5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD. PMID:27525107

  3. Single Nucleotide Polymorphism (SNP) in the Adiponectin Gene and Cardiovascular Disease.

    Chirumbolo, Salvatore

    2016-07-01

    Dear Editor, The recent article by Mohammadzadeh et al.[1] on the latest issue of this Journal showed that the T allele +276G/T SNP of ADIPOQ gene is more associated with the increasing risk of coronary artery disease (CAD) in subjects with type 2 diabetes. Adipocytes were described in myocardial tissue of CAD patients and their role recently discussed[2,3]. Susceptibility to CAD by polymorphism in the Q gene of adiponectin has been reported for 3'-UTR, which harbours some genetic loci associated with metabolic risks and atherosclerosis[4]. Actually, previous studies have shown that the haplotype SNP +276G>T was associated with a decreased risk of CAD, after adjustment for potential confounding factors, therefore some controversial opinion still exists[5]. This evidence should be associated with the role exerted by adipocytes and adiponectin in heart physiology. In particular, in hypertensive disorder complicating pregnancy (HDCP), by investigating the population frequency of alleles, genotypes, and haplotypes of two single nucleotide polymorphisms (SNPs), namely +45T>G (rs2241766) and +276G>T (rs1501299), some authors found that the SNP +276 TT genotype was significantly associated with protection against HDCP, when compared to the pooled G genotypes[6]. Moreover, the same +276G/T SNP haplotype was strongly associated with biliary atresia, an intractable neonatal inflammatory and obliterative cholangiopathy, leading to progressive fibrosis and cirrhosis[7]. CAD is closely related to adiponectin biology. The same isoforms of adiponectin seem to be not associated to CAD severity but to glucose metabolism and its impairment[8]. In the paper by Mohammadzadeh et al.[1], T allele in +276G/T SNP haplotype is highly associated with CAD in subjects with type 2 diabetes, but this linkage should be reappraised if related much more to diabetes rather than CAD. Association of T allele in the indicated SNP with CAD may be an indirect consequence of type 2 diabetes, as reported

  4. Genome-wide identification of significant aberrations in cancer genome

    Yuan Xiguo

    2012-07-01

    Full Text Available Abstract Background Somatic Copy Number Alterations (CNAs in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC, a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1 exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2 performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3 iteratively detecting Significant Copy Number Aberrations (SCAs and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. Results We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma. When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC or tumor suppressor genes (e.g., CDKN2A/B. Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. Conclusions Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes

  5. Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii

    Thomas Julie

    2010-02-01

    Full Text Available Abstract Background Genome-wide computational analysis of alternative splicing (AS in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs. Results Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy. Conclusions The extent of AS in Chlamydomonas that we observed is much

  6. Genome-wide selection signatures in Pinzgau cattle

    Radovan Kasarda

    2015-08-01

    Full Text Available The aim of this study was to identify the evidence of recent selection based on estimation of the integrated Haplotype Score (iHS, population differentiation index (FST and characterize affected regions near QTL associated with traits under strong selection in Pinzgau cattle. In total 21 Austrian and 19 Slovak purebreed bulls genotyped with Illumina bovineHD and  bovineSNP50 BeadChip were used to identify genomic regions under selection. Only autosomal loci with call rate higher than 90%, minor allele frequency higher than 0.01 and Hardy-Weinberg equlibrium limit of 0.001 were included in the subsequent analyses of selection sweeps presence. The final dataset was consisted from 30538 SNPs with 81.86 kb average adjacent SNPs spacing. The iHS score were averaged into non-overlapping 500 kb segments across the genome. The FST values were also plotted against genome position based on sliding windows approach and averaged over 8 consecutive SNPs. Based on integrated Haplotype Score evaluation only 7 regions with iHS score higher than 1.7 was found. The average iHS score observed for each adjacent syntenic regions indicated slight effect of recent selection in analysed group of Pinzgau bulls. The level of genetic differentiation between Austrian and Slovak bulls estimated based on FST index was low. Only 24% of FST values calculated for each SNP was greather than 0.01. By using sliding windows approach was found that 5% of analysed windows had higher value than 0.01. Our results indicated use of similar selection scheme in breeding programs of Slovak and Austrian Pinzgau bulls. The evidence for genome-wide association between signatures of selection and regions affecting complex traits such as milk production was insignificant, because the loci in segments identified as affected by selection were very distant from each other. Identification of genomic regions that may be under pressure of selection for phenotypic traits to better understanding of the

  7. Genome-wide linkage analyses of two repetitive behavior phenotypes in Utah pedigrees with autism spectrum disorders

    Cannon Dale S

    2010-02-01

    Full Text Available Abstract Background It has been suggested that efforts to identify genetic risk markers of autism spectrum disorder (ASD would benefit from the analysis of more narrowly defined ASD phenotypes. Previous research indicates that 'insistence on sameness' (IS and 'repetitive sensory-motor actions' (RSMA are two factors within the ASD 'repetitive and stereotyped behavior' domain. The primary aim of this study was to identify genetic risk markers of both factors to allow comparison of those markers with one another and with markers found in the same set of pedigrees using ASD diagnosis as the phenotype. Thus, we empirically addresses the possibilities that more narrowly defined phenotypes improve linkage analysis signals and that different narrowly defined phenotypes are associated with different loci. Secondary aims were to examine the correlates of IS and RSMA and to assess the heritability of both scales. Methods A genome-wide linkage analysis was conducted with a sample of 70 multiplex ASD pedigrees using IS and RSMA as phenotypes. Genotyping services were provided by the Center for Inherited Disease Research using the 6 K single nucleotide polymorphism linkage panel. Analysis was done using the multipoint linkage software program MCLINK, a Markov chain Monte Carlo (MCMC method that allows for multilocus linkage analysis on large extended pedigrees. Results Genome-wide significance was observed for IS at 2q37.1-q37.3 (dominant model heterogeneity lod score (hlod 3.42 and for RSMA at 15q13.1-q14 (recessive model hlod 3.93. We found some linkage signals that overlapped and others that were not observed in our previous linkage analysis of the ASD phenotype in the same pedigrees, and regions varied in the range of phenotypes with which they were linked. A new finding with respect to IS was that it is positively associated with IQ if the IS-RSMA correlation is statistically controlled. Conclusions The finding that IS and RSMA are linked to different

  8. A 2cM genome-wide scan of European Holstein cattle affected by classical BSE

    Prasad Aparna

    2010-03-01

    Full Text Available Abstract Background Classical bovine spongiform encephalopathy (BSE is an acquired prion disease that is invariably fatal in cattle and has been implicated as a significant human health risk. Polymorphisms that alter the prion protein of sheep or humans have been associated with variations in transmissible spongiform encephalopathy susceptibility or resistance. In contrast, there is no strong evidence that non-synonymous mutations in the bovine prion gene (PRNP are associated with classical BSE disease susceptibility. However, two bovine PRNP insertion/deletion polymorphisms, one within the promoter region and the other in intron 1, have been associated with susceptibility to classical BSE. These associations do not explain the full extent of BSE susceptibility, and loci outside of PRNP appear to be associated with disease incidence in some cattle populations. To test for associations with BSE susceptibility, we conducted a genome wide scan using a panel of 3,072 single nucleotide polymorphism (SNP markers on 814 animals representing cases and control Holstein cattle from the United Kingdom BSE epidemic. Results Two sets of BSE affected Holstein cattle were analyzed in this study, one set with known family relationships and the second set of paired cases with controls. The family set comprises half-sibling progeny from six sires. The progeny from four of these sires had previously been scanned with microsatellite markers. The results obtained from the current analysis of the family set yielded both some supporting and new results compared with those obtained in the earlier study. The results revealed 27 SNPs representing 18 chromosomes associated with incidence of BSE disease. These results confirm a region previously reported on chromosome 20, and identify additional regions on chromosomes 2, 14, 16, 21 and 28. This study did not identify a significant association near the PRNP in the family sample set. The only association found in the PRNP

  9. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  10. Quality control and conduct of genome-wide association meta-analyses

    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C;

    2014-01-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) Q...

  11. Dating the age of admixture via wavelet transform analysis of genome-wide data

    I. Pugach (Irina); R. Matveyev (Rostislav); A. Wollstein (Andreas); M.H. Kayser (Manfred); M. Stoneking (Mark)

    2011-01-01

    textabstractWe describe a PCA-based genome scan approach to analyze genome-wide admixture structure, and introduce wavelet transform analysis as a method for estimating the time of admixture. We test the wavelet transform method with simulations and apply it to genome-wide SNP data from eight admixe

  12. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2010-01-01

    Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of…

  13. Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J. L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schafer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genome-wide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases…

  14. Evaluating variations of genotype calling: a potential source of spurious associations in genome-wide association studies

    Xuixiao Hong; Zhenqiang Su; Weigong Ge; Leming Shi; Roger Perkins; Hong Fang; Donna Mendrick; Weida Tong

    2010-04-01

    Genome-wide association studies (GWAS) examine the entire human genome with the goal of identifying genetic variants (usually single nucleotide polymorphisms (SNPs)) that are associated with phenotypic traits such as disease status and drug response. The discordance of significantly associated SNPs for the same disease identified from different GWAS indicates that false associations exist in such results. In addition to the possible sources of spurious associations that have been investigated and discussed intensively, such as sample size and population stratification, an accurate and reproducible genotype calling algorithm is required for concordant GWAS results from different studies. However, variations of genotype calling of an algorithm and their effects on significantly associated SNPs identified in downstream association analyses have not been systematically investigated. In this paper, the variations of genotype calling using the Bayesian Robust Linear Model with Mahalanobis distance classifier (BRLMM) algorithm and the resulting influence on the lists of significantly associated SNPs were evaluated using the raw data of 270 HapMap samples analysed with the Affymetrix Human Mapping 500K Array Set (Affy500K) by changing algorithmic parameters. Modified were the Dynamic Model (DM) call confidence threshold (threshold) and the number of randomly selected SNPs (size). Comparative analysis of the calling results and the corresponding lists of significantly associated SNPs identified through association analysis revealed that algorithmic parameters used in BRLMM affected the genotype calls and the significantly associated SNPs. Both the threshold and the size affected the called genotypes and the lists of significantly associated SNPs in association analysis. The effect of the threshold was much larger than the effect of the size. Moreover, the heterozygous calls had lower consistency compared to the homozygous calls.

  15. Detection of genome-wide polymorphisms in the AT-rich Plasmodium falciparum genome using a high-density microarray

    Huyen Yentram

    2008-08-01

    Full Text Available Abstract Background Genetic mapping is a powerful method to identify mutations that cause drug resistance and other phenotypic changes in the human malaria parasite Plasmodium falciparum. For efficient mapping of a target gene, it is often necessary to genotype a large number of polymorphic markers. Currently, a community effort is underway to collect single nucleotide polymorphisms (SNP from the parasite genome. Here we evaluate polymorphism detection accuracy of a high-density 'tiling' microarray with 2.56 million probes by comparing single feature polymorphisms (SFP calls from the microarray with known SNP among parasite isolates. Results We found that probe GC content, SNP position in a probe, probe coverage, and signal ratio cutoff values were important factors for accurate detection of SFP in the parasite genome. We established a set of SFP calling parameters that could predict mSFP (SFP called by multiple overlapping probes with high accuracy (≥ 94% and identified 121,087 mSFP genome-wide from five parasite isolates including 40,354 unique mSFP (excluding those from multi-gene families and ~18,000 new mSFP, producing a genetic map with an average of one unique mSFP per 570 bp. Genomic copy number variation (CNV among the parasites was also cataloged and compared. Conclusion A large number of mSFP were discovered from the P. falciparum genome using a high-density microarray, most of which were in clusters of highly polymorphic genes at chromosome ends. Our method for accurate mSFP detection and the mSFP identified will greatly facilitate large-scale studies of genome variation in the P. falciparum parasite and provide useful resources for mapping important parasite traits.

  16. Genome-wide SNP validation and mantle tissue transcriptome analysis in the silver-lipped pearl oyster, Pinctada maxima.

    Jones, David B; Jerry, Dean R; Forêt, Sylvain; Konovalov, Dmitry A; Zenger, Kyall R

    2013-12-01

    Pearl oysters are not only farmed for their gemstone quality pearls worldwide, but they are also becoming important model organisms for investigating genetic mechanisms of biomineralisation. Despite their economic and scientific significance, limited genomic resources are available for this important group of bivalves, hampering investigations into identifying genes that regulate important pearl quality traits and unique biological characteristics (i.e. biomineralisation). The silver-lipped pearl oyster, Pinctada maxima, is one species where there is interest in understanding genes that regulate commercially important pearl traits, but presently, there is a dearth of genomic information. The objective of this study was to develop and validate a large number of type I genome-wide single nucleotide polymorphisms (SNPs) for P. maxima suitable for high-throughput genotyping. In addition, sequence annotations and Gene Ontology terms were assigned to a large mantle tissue 454 expressed sequence tag assembly (96,794 contigs) and information on known bivalve biomineralisation genes was incorporated into SNP discovery. The SNP discovery effort resulted in the de novo identification of 172,625 SNPs, of which 9,108 were identified as high value [minor allele frequency (MAF)≥ 0.15, read depth  ≥ 8]. Validation of 2,782 of these SNPs using Illumina iSelect Infinium genotyping technology returned some of the highest assay conversion (86.6 %) and validation (59.9 %; mean MAF 0.28) rates observed in aquaculture species to date. Genomic resources presented here will be pivotal to future research investigating the biological mechanisms behind biomineralisation and will form a strong foundation for genetic selective breeding programs in the P. maxima pearling industry. PMID:23715808

  17. Genome-wide association study (GWAS for growth rate and age at sexual maturation in Atlantic salmon (Salmo salar.

    Alejandro P Gutierrez

    Full Text Available Early sexual maturation is considered a serious drawback for Atlantic salmon aquaculture as it retards growth, increases production times and affects flesh quality. Although both growth and sexual maturation are thought to be complex processes controlled by several genetic and environmental factors, selection for these traits has been continuously accomplished since the beginning of Atlantic salmon selective breeding programs. In this genome-wide association study (GWAS we used a 6.5K single-nucleotide polymorphism (SNP array to genotype ∼ 480 individuals from the Cermaq Canada broodstock program and search for SNPs associated with growth and age at sexual maturation. Using a mixed model approach we identified markers showing a significant association with growth, grilsing (early sexual maturation and late sexual maturation. The most significant associations were found for grilsing, with markers located in Ssa10, Ssa02, Ssa13, Ssa25 and Ssa12, and for late maturation with markers located in Ssa28, Ssa01 and Ssa21. A lower level of association was detected with growth on Ssa13. Candidate genes, which were linked to these genetic markers, were identified and some of them show a direct relationship with developmental processes, especially for those in association with sexual maturation. However, the relatively low power to detect genetic markers associated with growth (days to 5 kg in this GWAS indicates the need to use a higher density SNP array in order to overcome the low levels of linkage disequilibrium observed in Atlantic salmon before the information can be incorporated into a selective breeding program.

  18. Genome-Wide Association Study (GWAS) for Growth Rate and Age at Sexual Maturation in Atlantic Salmon (Salmo salar)

    Gutierrez, Alejandro P.; Yáñez, José M.; Fukui, Steve; Swift, Bruce; Davidson, William S.

    2015-01-01

    Early sexual maturation is considered a serious drawback for Atlantic salmon aquaculture as it retards growth, increases production times and affects flesh quality. Although both growth and sexual maturation are thought to be complex processes controlled by several genetic and environmental factors, selection for these traits has been continuously accomplished since the beginning of Atlantic salmon selective breeding programs. In this genome-wide association study (GWAS) we used a 6.5K single-nucleotide polymorphism (SNP) array to genotype ∼480 individuals from the Cermaq Canada broodstock program and search for SNPs associated with growth and age at sexual maturation. Using a mixed model approach we identified markers showing a significant association with growth, grilsing (early sexual maturation) and late sexual maturation. The most significant associations were found for grilsing, with markers located in Ssa10, Ssa02, Ssa13, Ssa25 and Ssa12, and for late maturation with markers located in Ssa28, Ssa01 and Ssa21. A lower level of association was detected with growth on Ssa13. Candidate genes, which were linked to these genetic markers, were identified and some of them show a direct relationship with developmental processes, especially for those in association with sexual maturation. However, the relatively low power to detect genetic markers associated with growth (days to 5 kg) in this GWAS indicates the need to use a higher density SNP array in order to overcome the low levels of linkage disequilibrium observed in Atlantic salmon before the information can be incorporated into a selective breeding program. PMID:25757012

  19. Extended Analysis of a Genome-Wide Association Study in Primary Sclerosing Cholangitis Detects Multiple Novel Risk Loci

    Folseraas, Trine; Melum, Espen; Rausch, Philipp; Juran, Brian D.; Ellinghaus, Eva; Shiryaev, Alexey; Laerdahl, Jon K.; Ellinghaus, David; Schramm, Christoph; Weismüller, Tobias J.; Gotthardt, Daniel Nils; Hov, Johannes Roksund; Clausen, Ole Petter; Weersma, Rinse K.; Janse, Marcel; Boberg, Kirsten Muri; Björnsson, Einar; Marschall, Hanns-Ulrich; Cleynen, Isabelle; Rosenstiel, Philip; Holm, Kristian; Teufel, Andreas; Rust, Christian; Gieger, Christian; Wichmann, H-Erich; Bergquist, Annika; Ryu, Euijung; Ponsioen, Cyriel Y.; Runz, Heiko; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Wijmenga, Cisca; Schrumpf, Erik; Manns, Michael P.; Lazaridis, Konstantinos N.; Schreiber, Stefan; Baines, John F.; Franke, Andre; Karlsen, Tom H.

    2012-01-01

    Background & Aims A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (Preplication<0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; Pcombined=2.1×10−8) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (Prepl<0.05). FUT2 at chromosome 19q13 (rs602662; Pcomb=1.9×10−6, rs281377; Pcomb = 2.1×10−6 and rs601338; Pcomb=2.7×10−6) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influences biliary microbial community composition in PSC patients. Conclusions We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence from microbiota on biliary pathology in PSC. PMID:22521342

  20. Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system

    Jing eJiang

    2013-08-01

    Full Text Available The mammalian target of rapamycin (mTOR inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA analyses involving single nucleotide polymorphisms (SNPs, mRNA and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs. Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. 127 and 100 SNPs had P<10-4, while 8 and 10 SNPs had P<10-5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.

  1. A genome-wide approach to screen for genetic variants in broilers (Gallus gallus) with divergent feed conversion ratio.

    Shah, Tejas M; Patel, Namrata V; Patel, Anand B; Upadhyay, Maulik R; Mohapatra, Amitbikram; Singh, Krishna M; Deshpande, Sunil D; Joshi, Chaitanya G

    2016-08-01

    Feed conversion ratio (FCR) is an economically important trait in broilers and feed accounts for a significant proportion of the costs involved in broiler production. To explore the contribution of functional variants to FCR trait, we analyzed coding and non-coding single-nucleotide variants (SNVs) across the genome by exome sequencing in seven pairs of full-sibs broilers with divergent FCR and with a sequence coverage at an average depth of fourfold. We identified 192,119 high-quality SNVs, including 30,380 coding SNVs (cSNVs) in the experimental population. We discovered missense SNVs in PGM2, NOX4, TGFBR3, and TMX4, and synonymous SNVs in TSNAX, ITA, HSP90B1, and COL18A1 associated with FCR. Haplotype analyses of genome-wide significant SNVs in PGM2, PHKG1, DGKZ, and SOD2 were also observed with suggestive evidence of haplotype association with FCR. Single-variant and FCR QTL-related genes-based association analyses of SNVs identified newly associated genes for FCR in the regions subjected to targeted exome sequencing. The top seven SNVs were next evaluated in independent replication data sets where SNV chr. 3: 13,990,160 (c. 961G>C) at TMX4 was replicated (p < 0.05). Collectively, we have detected SNVs associated with FCR in broiler as well as identification of SNVs in known FCR QTL region. These findings should facilitate the discovery of causative variants for FCR and contribute to marker-assisted selection. PMID:27174137

  2. Identification of novel susceptibility Loci for kawasaki disease in a Han chinese population by a genome-wide association study.

    Fuu-Jen Tsai

    Full Text Available Kawasaki disease (KD is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS in 250 KD patients and 446 controls in a Han Chinese population residing in Taiwan, and further validated our findings in an independent Han Chinese cohort of 208 cases and 366 controls. The most strongly associated single-nucleotide polymorphisms (SNPs detected in the joint analysis corresponded to three novel loci. Among these KD-associated SNPs three were close to the COPB2 (coatomer protein complex beta-2 subunit gene: rs1873668 (p = 9.52×10⁻⁵, rs4243399 (p = 9.93×10⁻⁵, and rs16849083 (p = 9.93×10⁻⁵. We also identified a SNP in the intronic region of the ERAP1 (endoplasmic reticulum amino peptidase 1 gene (rs149481, p(best = 4.61×10⁻⁵. Six SNPs (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667 clustered in an area containing immunoglobulin heavy chain variable regions genes, with p(best-values between 2.08×10⁻⁵ and 8.93×10⁻⁶, were also identified. This is the first KD GWAS performed in a Han Chinese population. The novel KD candidates we identified have been implicated in T cell receptor signaling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses. These findings may lead to a better understanding of the underlying molecular pathogenesis of KD.

  3. Genome wide analysis indicates genes for basement membrane and cartilage matrix proteins as candidates for hip dysplasia in Labrador Retrievers.

    Ineke C M Lavrijsen

    Full Text Available Hip dysplasia, an abnormal laxity of the hip joint, is seen in humans as well as dogs and is one of the most common skeletal disorders in dogs. Canine hip dysplasia is considered multifactorial and polygenic, and a variety of chromosomal regions have been associated with the disorder. We performed a genome-wide association study in Dutch Labrador Retrievers, comparing data of nearly 18,000 single nucleotide polymorphisms (SNPs in 48 cases and 30 controls using two different statistical methods. An individual SNP analysis based on comparison of allele frequencies with a χ(2 statistic was used, as well as a simultaneous SNP analysis based on Bayesian variable selection. Significant association with canine hip dysplasia was observed on chromosome 8, as well as suggestive association on chromosomes 1, 5, 15, 20, 25 and 32. Next-generation DNA sequencing of the exons of genes of seven regions identified multiple associated alleles on chromosome 1, 5, 8, 20, 25 and 32 (p<0.001. Candidate genes located in the associated regions on chromosomes 1, 8 and 25 included LAMA2, LRR1 and COL6A3, respectively. The associated region on CFA20 contained candidate genes GDF15, COMP and CILP2. In conclusion, our study identified candidate genes that might affect susceptibility to canine hip dysplasia. These genes are involved in hypertrophic differentiation of chondrocytes and extracellular matrix integrity of basement membrane and cartilage. The functions of the genes are in agreement with the notion that disruptions in endochondral bone formation in combination with soft tissue defects are involved in the etiology of hip dysplasia.

  4. Characterization of a REST-Regulated Internal Promoter in the Schizophrenia Genome-Wide Associated Gene MIR137.

    Warburton, Alix; Breen, Gerome; Rujescu, Dan; Bubb, Vivien J; Quinn, John P

    2015-05-01

    MIR137 has been identified as a candidate gene for schizophrenia from genome-wide association studies via association with an intronic single nucleotide polymorphism (SNP), rs1625579. The location of the SNP suggests one mechanism in which transcriptional or posttranscriptional regulation of miR-137 expression could underlie schizophrenia. We identified and validated a novel promoter of the MIR137 gene adjacent to miR-137 itself which can direct the expression of distinct mRNA isoforms encoding miR-137. Analysis of both endogenous gene expression and reporter gene assays determined that this internal promoter is regulated by repressor element-1 silencing transcription factor (REST), which has previously been associated with pathways linked to schizophrenia. Distinct isoforms of REST mediate differential expression at this locus, suggesting the relative levels of these isoforms are important for miR-137 expression profiles. The internal promoter contains a variable number tandem repeat (VNTR) domain adjacent to the pre-miR-137 sequence. The reporter gene activity directed by this promoter was modified by the genotype of the VNTR. Differential expression was also observed in response to cocaine, which is known to regulate the REST pathway in SH-SY5Y cells. Our data support the hypothesis that a "gene × environment" interaction could modify the level of miR-137 expression via this internal promoter and that the genotype of the VNTR could modulate transcriptional responses. We demonstrate that this promoter region is not in disequilibrium with rs1625579 and therefore would supply a distinct pathway to potentially alter miR-137 levels in response to environmental cues. PMID:25154622

  5. A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

    Villard, Eric; Perret, Claire; Gary, Françoise; Proust, Carole; Dilanian, Gilles; Hengstenberg, Christian; Ruppert, Volker; Arbustini, Eloisa; Wichter, Thomas; Germain, Marine; Dubourg, Olivier; Tavazzi, Luigi; Aumont, Marie-Claude; DeGroote, Pascal; Fauchier, Laurent; Trochu, Jean-Noël; Gibelin, Pierre; Aupetit, Jean-François; Stark, Klaus; Erdmann, Jeanette; Hetzer, Roland; Roberts, Angharad M.; Barton, Paul J.R.; Regitz-Zagrosek, Vera; Aslam, Uzma; Duboscq-Bidot, Laëtitia; Meyborg, Matthias; Maisch, Bernhard; Madeira, Hugo; Waldenström, Anders; Galve, Enrique; Cleland, John G.; Dorent, Richard; Roizes, Gerard; Zeller, Tanja; Blankenberg, Stefan; Goodall, Alison H.; Cook, Stuart; Tregouet, David A.; Tiret, Laurence; Isnard, Richard; Komajda, Michel; Charron, Philippe; Cambien, François

    2011-01-01

    Aims Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. Methods and results One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10−7), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. Conclusion This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM. PMID:21459883

  6. Genome-wide Association Study to Identify Quantitative Trait Loci for Meat and Carcass Quality Traits in Berkshire.

    Iqbal, Asif; Kim, You-Sam; Kang, Jun-Mo; Lee, Yun-Mi; Rai, Rajani; Jung, Jong-Hyun; Oh, Dong-Yup; Nam, Ki-Chang; Lee, Hak-Kyo; Kim, Jong-Joo

    2015-11-01

    Meat and carcass quality attributes are of crucial importance influencing consumer preference and profitability in the pork industry. A set of 400 Berkshire pigs were collected from Dasan breeding farm, Namwon, Chonbuk province, Korea that were born between 2012 and 2013. To perform genome wide association studies (GWAS), eleven meat and carcass quality traits were considered, including carcass weight, backfat thickness, pH value after 24 hours (pH24), Commission Internationale de l'Eclairage lightness in meat color (CIE L), redness in meat color (CIE a), yellowness in meat color (CIE b), filtering, drip loss, heat loss, shear force and marbling score. All of the 400 animals were genotyped with the Porcine 62K SNP BeadChips (Illumina Inc., USA). A SAS general linear model procedure (SAS version 9.2) was used to pre-adjust the animal phenotypes before GWAS with sire and sex effects as fixed effects and slaughter age as a covariate. After fitting the fixed and covariate factors in the model, the residuals of the phenotype regressed on additive effects of each single nucleotide polymorphism (SNP) under a linear regression model (PLINK version 1.07). The significant SNPs after permutation testing at a chromosome-wise level were subjected to stepwise regression analysis to determine the best set of SNP markers. A total of 55 significant (peffect were also identified. A pair of significant QTL for pH24 was also found to affect both CIE L and drip loss percentage. The significant QTL after characterization of the functional candidate genes on the QTL or around the QTL region may be effectively and efficiently used in marker assisted selection to achieve enhanced genetic improvement of the trait considered. PMID:26580276

  7. A genome-wide search for quantitative trait loci affecting the cortical surface area and thickness of Heschl's gyrus.

    Cai, D-C; Fonteijn, H; Guadalupe, T; Zwiers, M; Wittfeld, K; Teumer, A; Hoogman, M; Arias-Vásquez, A; Yang, Y; Buitelaar, J; Fernández, G; Brunner, H G; van Bokhoven, H; Franke, B; Hegenscheid, K; Homuth, G; Fisher, S E; Grabe, H J; Francks, C; Hagoort, P

    2014-09-01

    Heschl's gyrus (HG) is a core region of the auditory cortex whose morphology is highly variable across individuals. This variability has been linked to sound perception ability in both speech and music domains. Previous studies show that variations in morphological features of HG, such as cortical surface area and thickness, are heritable. To identify genetic variants that affect HG morphology, we conducted a genome-wide association scan (GWAS) meta-analysis in 3054 healthy individuals using HG surface area and thickness as quantitative traits. None of the single nucleotide polymorphisms (SNPs) showed association P values that would survive correction for multiple testing over the genome. The most significant association was found between right HG area and SNP rs72932726 close to gene DCBLD2 (3q12.1; P=2.77 × 10(-7) ). This SNP was also associated with other regions involved in speech processing. The SNP rs333332 within gene KALRN (3q21.2; P=2.27 × 10(-6) ) and rs143000161 near gene COBLL1 (2q24.3; P=2.40 × 10(-6) ) were associated with the area and thickness of left HG, respectively. Both genes are involved in the development of the nervous system. The SNP rs7062395 close to the X-linked deafness gene POU3F4 was associated with right HG thickness (Xq21.1; P=2.38 × 10(-6) ). This is the first molecular genetic analysis of variability in HG morphology. PMID:25130324

  8. Integrative pathway analysis of a genome-wide association study of V̇o2max response to exercise training

    Vivar, Juan C.; Sarzynski, Mark A.; Sung, Yun Ju; Timmons, James A.; Bouchard, Claude; Rankinen, Tuomo

    2013-01-01

    We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (V̇o2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies V̇o2maxtrainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to V̇o2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in V̇o2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation. PMID:23990238

  9. Single nucleotide polymorphisms (SNPs) that map to gaps in the human SNP map

    Tsui, Circe; Coleman, Laura E.; Griffith, Jacqulyn L.; Bennett, E. Andrew; Goodson, Summer G.; Scott, Jason D.; Pittard, W. Stephen; Devine, Scott E.

    2003-01-01

    An international effort is underway to generate a comprehensive haplotype map (HapMap) of the human genome represented by an estimated 300 000 to 1 million ‘tag’ single nucleotide polymorphisms (SNPs). Our analysis indicates that the current human SNP map is not sufficiently dense to support the HapMap project. For example, 24.6% of the genome currently lacks SNPs at the minimal density and spacing that would be required to construct even a conservative tag SNP map containing 300 000 SNPs. In...

  10. Single-nucleotide polymorphism analysis of GH, GHR, and IGF-1 genes in minipigs

    Y.G. Tian; Yue, M.; Gu, Y; Gu, W.W.; Wang, Y.J.

    2014-01-01

    Tibetan (TB) and Bama (BM) miniature pigs are two popular pig breeds that are used as experimental animals in China due to their small body size. Here, we analyzed single-nucleotide polymorphisms (SNPs) in gene fragments that are closely related to growth traits [growth hormone (GH), growth hormone receptor (GHR), and insulin-like growth factor (IGF)-1)] in these pig breeds and a large white (LW) control pig breed. On the basis of the analysis of 100 BMs, 108 TBs, and 50 LWs, the polymorphic ...

  11. Electrochemical detection of single nucleotide polymorphisms using enzyme-linked assay

    Horáková Brázdilová, Petra; Šimková, Eva; Vychodilová, Zdenka; Brázdová, Marie; Vytřas, K.; Fojta, Miroslav

    Jětřichovice, 2009. s. 36-37. ISBN 978-80-254-3997-5. [XXIX. Moderní elektrochemické metody. 25.05.2009-29.05.2009, Jetřichovice] R&D Projects: GA MŠk(CZ) LC06035; GA ČR(CZ) GA203/07/1195 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : single nucleotide polymorphism * primer extension * carbon electrode Subject RIV: BO - Biophysics

  12. Loss of heterozygosity analyzed by single nucleotide polymorphisrn array in cancer

    HaiTao Zheng; ZhiHai Peng; Sheng Li; Lin He

    2005-01-01

    Neoplastic progression is generally characterized by the accumulation of multiple genetic alterations including loss of tumor suppression gene function.Loss of heterozygosity (LOH) has been used to identify genomic regions that harbor tumor suppressor genes and to characterize different tumor types, pathological stages and progression. LOH pattern has been detected by allelotyping using restriction fragment length polymorphism, and later by simple sequence length polymorphisms (SSLPs or microsatellite) for 10 years.This paper reviews the detection of LOH by recently developed single nucleotide polymorphism (SNP) arrays (all analyzed by Affymetrix array); furthermore, its advantage and disadvantage were analyzed in several kinds of cancer.

  13. Mining for single nucleotide polymorphisms and insertions / deletions in expressed sequence tag libraries of oil palm

    Riju, Aykkal; Chandrasekar, Arumugam; Arunachalam, Vadivel

    2007-01-01

    The oil palm is a tropical oil bearing tree. Recently EST-derived SNPs and SSRs are a free by-product of the currently expanding EST (Expressed Sequence Tag) data bases. The development of high-throughput methods for the detection of SNPs (Single Nucleotide Polymorphism) and small indels (insertion / deletion) has led to a revolution in their use as molecular markers. Available (5452) Oil palm EST sequences were mined from dbEST of NCBI. CAP3 program was used to assemble EST sequences into co...

  14. Distribution of Fitness and Virulence Effects Caused by Single-Nucleotide Substitutions in Tobacco Etch Virus▿ †

    Carrasco, Purificación; De La Iglesia, Francisca; Elena, Santiago F.

    2007-01-01

    Little is known about the fitness and virulence consequences of single-nucleotide substitutions in RNA viral genomes, and most information comes from the analysis of nonrandom sets of mutations with strong phenotypic effect or which have been assessed in vitro, with their relevance in vivo being unclear. Here we used site-directed mutagenesis to create a collection of 66 clones of Tobacco etch potyvirus, each carrying a different, randomly chosen, single-nucleotide substitution. Competition e...

  15. SNP-based pathway enrichment analysis for genome-wide association studies

    Potkin Steven G

    2011-04-01

    Full Text Available Abstract Background Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs, have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. Results We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1 for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2 ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one

  16. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.

    Ying Liu

    2008-03-01

    Full Text Available A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS and psoriatic arthritis (PSA, inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA were genotyped with 311,398 single nucleotide polymorphisms (SNPs, and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC. The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11, GWA scan; P = 1.8x10(-30, replication; P = 1.8x10(-39, combined; U.K. PSA: P = 6.9x10(-11. However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26 in U.S. cases yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively. This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4; U.K. PSA: P = 8.0x10(-4; IL12B:rs6887695, U.S. PS, P = 5x10(-5 and U.K. PSA, P = 1.3x10(-3 and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001. Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP and conserved oligomeric golgi complex component 6 (COG6 genes on chromosome 13q13 (combined P = 2x10(-6 for rs7993214; OR = 0.71, the late cornified envelope gene cluster (LCE from the Epidermal Differentiation Complex (PSORS4 (combined P = 6.2x10(-5 for rs6701216; OR 1.45 and a region of LD at 15q21 (combined P = 2.9x10(-5 for rs

  17. Identification of Single Nucleotide Polymorphism on Growth Hormone Gene in Aceh Cattle

    E. M. Sari

    2013-04-01

    Full Text Available This research was aimed to identify the changes of nucleotide (Single Nucleotide Polymorphism growth hormone gene in the population of Aceh cattle. There were 44 samples of DNA sequenced, and a few samples from Gen Bank (M57764. Based on the analysis using MEGA program, it was identified one new mutation on exon five on 2230 bp in which C nucleotide turned into T nucleotide, and this was called Silent Mutation (Leusine–Leusine/ CTC–CTT. The frequency of Single Nucleotide Polymorphism (SNP genotype on 2230 bp (C/T was CC (0.36, TT (0.14 and CT (0.50. The genotype TT was not possessed by Aceh cattle from Saree, but possessed by those from Banda Aceh and Indrapuri. Chi-square test showed not significant differences in allele frequencies for three population. The frequency of genotype SNP on 2291 bp (A/C was AC (0.11 and CC (0.89. The frequency of allele C was higher than allele A and T.

  18. Toward Non-Enzymatic Ultrasensitive Identification of Single Nucleotide Polymorphisms by Optical Methods

    Kira Astakhova

    2014-07-01

    Full Text Available Single nucleotide polymorphisms (SNPs are single nucleotide variations which comprise the most wide spread source of genetic diversity in the genome. Currently, SNPs serve as markers for genetic predispositions, clinically evident disorders and diverse drug responses. Present SNP diagnostics are primarily based on enzymatic reactions in different formats including sequencing, polymerase-chain reaction (PCR and microarrays. In these assays, the enzymes are applied to address the required sensitivity and specificity when detecting SNP. On the other hand, the development of enzyme-free, simple and robust SNP sensing methods is in a constant focus in research and industry as such assays allow rapid and reproducible SNP diagnostics without the need for expensive equipment and reagents. An ideal method for detection of SNP would entail mixing a DNA or RNA target with a probe to directly obtain a signal. Current assays are still not fulfilling these requirements, although remarkable progress has been achieved in recent years. In this review, current SNP sensing approaches are described with a main focus on recently introduced direct, enzyme-free and ultrasensitive SNP sensing by optical methods.

  19. A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

    Roe Bruce A

    2007-04-01

    Full Text Available Abstract Background The long bone abnormality (lbab mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

  20. Corelation Between Single Nucleotide Polymorphisms in Mu Opioid Receptor Exon 2 and Stereotypic Behaviour in Sows

    LI Jianhong; BAO Jun; CUI Weiguo

    2008-01-01

    Three breeds of sows were observed to investigate the relationship between Single Nucleotide Polymorphisms (SNPs) in Mu Opioid Receptor (MOR) and stereotypic behaviour, such as, sham-chewing, bar biting and standing still in order to better understand the mechanism of stereotypic development of the animals in restrained conditions. MOR exon 2 partial sequences were amplified to analyze single nucleotide polymorphisms by PCR-SSCE One SNP, a silence mutant was found. A significant difference (P<0.01) was found in the frequency of genotypes in these 3 breeds where only the BB genotype, which was identical to that published in GenBank, was found in the Duroc breed, while no AA genotype was found in Landrace, 3 genotypes AA, BB and AB were found in Yorkshire. The result also indicated that the individuals with AA and AB genotypes tended to be more active in sham-chewing than those with the BB genotype (P<0.05). The overall results of this study suggested that sham-chewing of sows may be subjected to both genetic control and environmental conditions, but activity level was more likely to be affected by their environment. We can putatively draw the conclusion that MOR gene has effect on the sham-chewing behavioral traits of sow.

  1. Naked-eye fingerprinting of single nucleotide polymorphisms on psoriasis patients

    Valentini, Paola; Marsella, Alessandra; Tarantino, Paolo; Mauro, Salvatore; Baglietto, Silvia; Congedo, Maurizio; Paolo Pompa, Pier

    2016-05-01

    We report a low-cost test, based on gold nanoparticles, for the colorimetric (naked-eye) fingerprinting of a panel of single nucleotide polymorphisms (SNPs), relevant for the personalized therapy of psoriasis. Such pharmacogenomic tests are not routinely performed on psoriasis patients, due to the high cost of standard technologies. We demonstrated high sensitivity and specificity of our colorimetric test by validating it on a cohort of 30 patients, through a double-blind comparison with two state-of-the-art instrumental techniques, namely reverse dot blotting and sequencing, finding 100% agreement. This test offers high parallelization capabilities and can be easily generalized to other SNPs of clinical relevance, finding broad utility in diagnostics and pharmacogenomics.We report a low-cost test, based on gold nanoparticles, for the colorimetric (naked-eye) fingerprinting of a panel of single nucleotide polymorphisms (SNPs), relevant for the personalized therapy of psoriasis. Such pharmacogenomic tests are not routinely performed on psoriasis patients, due to the high cost of standard technologies. We demonstrated high sensitivity and specificity of our colorimetric test by validating it on a cohort of 30 patients, through a double-blind comparison with two state-of-the-art instrumental techniques, namely reverse dot blotting and sequencing, finding 100% agreement. This test offers high parallelization capabilities and can be easily generalized to other SNPs of clinical relevance, finding broad utility in diagnostics and pharmacogenomics. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr02200f

  2. The evolution of lineage-specific clusters of single nucleotide substitutions in the human genome.

    Xu, Ke; Wang, Jianrong; Elango, Navin; Yi, Soojin V

    2013-10-01

    Genomic regions harboring large numbers of human-specific single nucleotide substitutions are of significant interest since they are potential genomic foci underlying the evolution of human-specific traits as well as human adaptive evolution. Previous studies aimed to identify such regions either used pre-defined genomic locations such as coding sequences and conserved genomic elements or employed sliding window methods. Such approaches may miss clusters of substitutions occurring in regions other than those pre-defined locations, or not be able to distinguish human-specific clusters of substitutions from regions of generally high substitution rates. Here, we conduct a 'maximal segment' analysis to scan the whole human genome to identify clusters of human-specific substitutions that occurred since the divergence of the human and the chimpanzee genomes. This method can identify species-specific clusters of substitutions while not relying on pre-defined regions. We thus identify thousands of clusters of human-specific single nucleotide substitutions. The evolution of such clusters is driven by a combination of several different evolutionary processes including increased regional mutation rate, recombination-associated processes, and positive selection. These newly identified regions of human-specific substitution clusters include large numbers of previously identified human accelerated regions, and exhibit significant enrichments of genes involved in several developmental processes. Our study provides a useful tool to study the evolution of the human genome. PMID:23770436

  3. Gene-gene, gene-environment, gene-nutrient interactionsand single nucleotide polymorphisms of inflammatorycytokines

    2015-01-01

    Inflammation plays a significant role in the etiologyof type 2 diabetes mellitus (T2DM). The rise in thepro-inflammatory cytokines is the essential step inglucotoxicity and lipotoxicity induced mitochondrialinjury, oxidative stress and beta cell apoptosis inT2DM. Among the recognized markers are interleukin(IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha(TNF-α), C-reactive protein, resistin, adiponectin, tissueplasminogen activator, fibrinogen and heptoglobins.Diabetes mellitus has firm genetic and very strongenvironmental influence; exhibiting a polygenic modeof inheritance. Many single nucleotide polymorphisms(SNPs) in various genes including those of pro and antiinflammatorycytokines have been reported as a riskfor T2DM. Not all the SNPs have been confirmed byunifying results in different studies and wide variationshave been reported in various ethnic groups. Theinter-ethnic variations can be explained by the factthat gene expression may be regulated by gene-gene,gene-environment and gene-nutrient interactions. Thisreview highlights the impact of these interactions ondetermining the role of single nucleotide polymorphismof IL-6, TNF-α, resistin and adiponectin in pathogenesisof T2DM.

  4. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

    Brandon L Pierce

    Full Text Available Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8 for percentages of both monomethylarsonic acid (MMA and dimethylarsinic acid (DMA near the AS3MT gene (arsenite methyltransferase; 10q24.32, with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity and 1,794 controls, we show that one of these five variants (rs9527 is also associated with skin lesion risk (P = 0.0005. Using a subset of individuals with prospectively measured arsenic (n = 769, we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01. Expression quantitative trait locus (eQTL analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12 and neighboring gene C10orf32 (P = 10(-44, which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical

  5. Exploiting SNP correlations within random forest for genome-wide association studies.

    Vincent Botta

    Full Text Available The primary goal of genome-wide association studies (GWAS is to discover variants that could lead, in isolation or in combination, to a particular trait or disease. Standard approaches to GWAS, however, are usually based on univariate hypothesis tests and therefore can account neither for correlations due to linkage disequilibrium nor for combinations of several markers. To discover and leverage such potential multivariate interactions, we propose in this work an extension of the Random Forest algorithm tailored for structured GWAS data. In terms of risk prediction, we show empirically on several GWAS datasets that the proposed T-Trees method significantly outperforms both the original Random Forest algorithm and standard linear models, thereby suggesting the actual existence of multivariate non-linear effects due to the combinations of several SNPs. We also demonstrate that variable importances as derived from our method can help identify relevant loci. Finally, we highlight the strong impact that quality control procedures may have, both in terms of predictive power and loci identification. Variable importance results and T-Trees source code are all available at www.montefiore.ulg.ac.be/~botta/ttrees/ and github.com/0asa/TTree-source respectively.

  6. Genome-wide transcription analysis of clinal genetic variation in Drosophila

    Chen, Ying; Lee, Siu F.; Blanc, Eric; Reuter, Caroline; Wertheim, Bregje; Martinez-Diaz, Pedro; Hoffmann, Ary A.; Partridge, Linda

    2012-01-01

    Clinal variation in quantitative traits is widespread, but its genetic basis awaits identification. Drosophila melanogaster shows adaptive, clinal variation in traits such as body size along latitudinal gradients on multiple continents. To investigate genome wide transcription differentiation betwee

  7. Pre-Steady-State Kinetic Analysis of Single-Nucleotide Incorporation by DNA Polymerases.

    Su, Yan; Peter Guengerich, F

    2016-01-01

    Pre-steady-state kinetic analysis is a powerful and widely used method to obtain multiple kinetic parameters. This protocol provides a step-by-step procedure for pre-steady-state kinetic analysis of single-nucleotide incorporation by a DNA polymerase. It describes the experimental details of DNA substrate annealing, reaction mixture preparation, handling of the RQF-3 rapid quench-flow instrument, denaturing polyacrylamide DNA gel preparation, electrophoresis, quantitation, and data analysis. The core and unique part of this protocol is the rationale for preparation of the reaction mixture (the ratio of the polymerase to the DNA substrate) and methods for conducting pre-steady-state assays on an RQF-3 rapid quench-flow instrument, as well as data interpretation after analysis. In addition, the methods for the DNA substrate annealing and DNA polyacrylamide gel preparation, electrophoresis, quantitation and analysis are suitable for use in other studies. © 2016 by John Wiley & Sons, Inc. PMID:27248785

  8. Bayesian estimation of genomic copy number with single nucleotide polymorphism genotyping arrays

    Davis Caleb

    2010-12-01

    Full Text Available Abstract Background The identification of copy number aberration in the human genome is an important area in cancer research. We develop a model for determining genomic copy numbers using high-density single nucleotide polymorphism genotyping microarrays. The method is based on a Bayesian spatial normal mixture model with an unknown number of components corresponding to true copy numbers. A reversible jump Markov chain Monte Carlo algorithm is used to implement the model and perform posterior inference. Results The performance of the algorithm is examined on both simulated and real cancer data, and it is compared with the popular CNAG algorithm for copy number detection. Conclusions We demonstrate that our Bayesian mixture model performs at least as well as the hidden Markov model based CNAG algorithm and in certain cases does better. One of the added advantages of our method is the flexibility of modeling normal cell contamination in tumor samples.

  9. Exploiting the CRISPR/Cas9 PAM Constraint for Single-Nucleotide Resolution Interventions.

    Yi Li

    Full Text Available CRISPR/Cas9 is an enabling RNA-guided technology for genome targeting and engineering. An acute DNA binding constraint of the Cas9 protein is the Protospacer Adjacent Motif (PAM. Here we demonstrate that the PAM requirement can be exploited to specifically target single-nucleotide heterozygous mutations while exerting no aberrant effects on the wild-type alleles. Specifically, we target the heterozygous G13A activating mutation of KRAS in colorectal cancer cells and we show reversal of drug resistance to a MEK small-molecule inhibitor. Our study introduces a new paradigm in genome editing and therapeutic targeting via the use of gRNA to guide Cas9 to a desired protospacer adjacent motif.

  10. Exploiting the CRISPR/Cas9 PAM Constraint for Single-Nucleotide Resolution Interventions

    Li, Yi; Mendiratta, Saurabh; Ehrhardt, Kristina; Kashyap, Neha; White, Michael A.; Bleris, Leonidas

    2016-01-01

    CRISPR/Cas9 is an enabling RNA-guided technology for genome targeting and engineering. An acute DNA binding constraint of the Cas9 protein is the Protospacer Adjacent Motif (PAM). Here we demonstrate that the PAM requirement can be exploited to specifically target single-nucleotide heterozygous mutations while exerting no aberrant effects on the wild-type alleles. Specifically, we target the heterozygous G13A activating mutation of KRAS in colorectal cancer cells and we show reversal of drug resistance to a MEK small-molecule inhibitor. Our study introduces a new paradigm in genome editing and therapeutic targeting via the use of gRNA to guide Cas9 to a desired protospacer adjacent motif. PMID:26788852

  11. Transcribed single nucleotide polymorphism: Ideal markers for detecting gene imprinting by 5' nuclease assay

    ZHU Guan-shan; WAN Mo-bin; ZHU Zhong-zheng; ZHENG Rui-ying

    2002-01-01

    Objective:To establish a novel approach for quick and highly efficient verification of human gene imprinting. Methods: A pair of dye-labelled probes, 5' nuclease assay was combined with RT-PCR to determine the genotype of a transcribed single nucleotide polymorphism (SNP) rs705 (C>T) of a known imprinted gene, small nuclear ribonucleotide protein N (SNRPN), on both genomic DNA and cDNA of human lymphoblast cell lines. Results: Allele discrimination showed a clear monoallelic expression pattern of SNRPN,which was confirmed by RT-PCR based restriction fragment length polymorphism (RFLPs). Pedigree analysis verified the paternal origin of expressed allele, which was in consistency with previous report. Conclusion: Transcribed SNP is an ideal marker for detecting gene imprinting by 5' nuclease assay. This approach also may be used to discover differential allele expression of non-imprinted genes, finding out gene cis-acting functional polymorphism.

  12. Relationships among calpastatin single nucleotide polymorphisms, calpastatin expression and tenderness in pork longissimus.

    Lindholm-Perry, A K; Rohrer, G A; Holl, J W; Shackelford, S D; Wheeler, T L; Koohmaraie, M; Nonneman, D

    2009-10-01

    Genome scans in the pig have identified a region on chromosome 2 (SSC2) associated with tenderness. Calpastatin is a likely positional candidate gene in this region because of its inhibitory role in the calpain system that is involved in postmortem tenderization. Novel single nucleotide polymorphisms (SNP) in calpastatin were identified and used to genotype a population (n = 1042) of Duroc-Landrace-Yorkshire swine for association with longissimus lumborum slice shear force (SSF) measured at days 7 and 14 postmortem. Three genetic markers residing in the calpastatin gene were significantly associated with SSF (P tenderness. In summary, these data provide evidence of several significant, publicly available SNP markers associated with SSF that may be useful to the swine industry for marker assisted selection of animals that have more tender meat. PMID:19422367

  13. Allele-specific amplification and electrochemiluminescence method for single nucleotide polymorphism analysis

    2007-01-01

    A new approach combined the specificity of allele-specific amplification (ASA) with the sensitivity of electrochemiluminescence (ECL) assay for single nucleotide polymorphism (SNP) analysis was proposed. Briefly, target gene was amplified by a biotin-labeled allele-specific forward primer and a Ru(bpy)32+ (TBR)-labeled universal reverse primer. Then, the amplicon was captured onto streptavidin-coated paramagnetic beads through biotin label, and detected by measuring the ECL signal of TBR label. Different genotypes were distinguished according to the ECL values of the amplicons by different genotypic primers. K-ras oncogene was used as a target to validate the feasibility of the method. The experiment results show that the different genotypes can be clearly distinguished by ASA-ECL assay. The method is useful in SNP analysis due to its sensitivity,safety, and simplicity.(C) 2007 Da Xing. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

  14. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma

    Palmer Lyle J

    2001-03-01

    Full Text Available Abstract Asthma is the most common chronic childhood disease in the developed nations, and is a complex disease that has high social and economic costs. Studies of the genetic etiology of asthma offer a way of improving our understanding of its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Considerable effort and expense have been expended in attempts to detect specific polymorphisms in genetic loci contributing to asthma susceptibility. Concomitantly, the technology for detecting single nucleotide polymorphisms (SNPs has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a method of investigating the genetic etiology of complex human diseases. This paper reviews both current and potential future contributions of SNPs to our understanding of asthma pathophysiology.

  15. Naked-eye fingerprinting of single nucleotide polymorphisms on psoriasis patients.

    Valentini, Paola; Marsella, Alessandra; Tarantino, Paolo; Mauro, Salvatore; Baglietto, Silvia; Congedo, Maurizio; Paolo Pompa, Pier

    2016-06-01

    We report a low-cost test, based on gold nanoparticles, for the colorimetric (naked-eye) fingerprinting of a panel of single nucleotide polymorphisms (SNPs), relevant for the personalized therapy of psoriasis. Such pharmacogenomic tests are not routinely performed on psoriasis patients, due to the high cost of standard technologies. We demonstrated high sensitivity and specificity of our colorimetric test by validating it on a cohort of 30 patients, through a double-blind comparison with two state-of-the-art instrumental techniques, namely reverse dot blotting and sequencing, finding 100% agreement. This test offers high parallelization capabilities and can be easily generalized to other SNPs of clinical relevance, finding broad utility in diagnostics and pharmacogenomics. PMID:27174795

  16. Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer

    Schildkraut, Joellen M; Goode, Ellen L; Clyde, Merlise A;

    2009-01-01

    The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2......,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in.......07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated...

  17. DivStat: a user-friendly tool for single nucleotide polymorphism analysis of genomic diversity.

    Inês Soares

    Full Text Available Recent developments have led to an enormous increase of publicly available large genomic data, including complete genomes. The 1000 Genomes Project was a major contributor, releasing the results of sequencing a large number of individual genomes, and allowing for a myriad of large scale studies on human genetic variation. However, the tools currently available are insufficient when the goal concerns some analyses of data sets encompassing more than hundreds of base pairs and when considering haplotype sequences of single nucleotide polymorphisms (SNPs. Here, we present a new and potent tool to deal with large data sets allowing the computation of a variety of summary statistics of population genetic data, increasing the speed of data analysis.

  18. Single-nucleotide polymorphisms among microRNA: big effects on cancer

    Feng-Ju Song; Ke-Xin Chen

    2011-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. Many miRNAs are found to play a significant role in cancer development either as tumor suppressor genes or as oncogenes. Examination of tumor-specific miRNA expression profiles in diverse cancers has revealed widespread deregulation of these molecules, whose loss and overexpression respectively have diagnostic and prognostic significance. Genetic variations, mostly single-nucleotide polymorphisms (SNPs) within miRNA sequences or their target sites, have been found to be associated with many kinds of cancers. In this review, we summarize the current knowledge of miRNAs including their biogenesis and role in cancer development, and finally, how SNPs among miRNAs affect miRNA biogenesis and contribute to cancer.

  19. Gallium plasmonic nanoparticles for label-free DNA and single nucleotide polymorphism sensing

    Marín, Antonio García; García-Mendiola, Tania; Bernabeu, Cristina Navio; Hernández, María Jesús; Piqueras, Juan; Pau, Jose Luis; Pariente, Félix; Lorenzo, Encarnación

    2016-05-01

    A label-free DNA and single nucleotide polymorphism (SNP) sensing method is described. It is based on the use of the pseudodielectric function of gallium plasmonic nanoparticles (GaNPs) deposited on Si (100) substrates under reversal of the polarization handedness condition. Under this condition, the pseudodielectric function is extremely sensitive to changes in the surrounding medium of the nanoparticle surface providing an excellent sensing platform competitive to conventional surface plasmon resonance. DNA sensing has been carried out by immobilizing a thiolated capture probe sequence from Helicobacter pylori onto GaNP/Si substrates; complementary target sequences of Helicobacter pylori can be quantified over the range of 10 pM to 3.0 nM with a detection limit of 6.0 pM and a linear correlation coefficient of R2 = 0.990. The selectivity of the device allows the detection of a single nucleotide polymorphism (SNP) in a specific sequence of Helicobacter pylori, without the need for a hybridization suppressor in solution such as formamide. Furthermore, it also allows the detection of this sequence in the presence of other pathogens, such as Escherichia coli in the sample. The broad applicability of the system was demonstrated by the detection of a specific gene mutation directly associated with cystic fibrosis in large genomic DNA isolated from blood cells.A label-free DNA and single nucleotide polymorphism (SNP) sensing method is described. It is based on the use of the pseudodielectric function of gallium plasmonic nanoparticles (GaNPs) deposited on Si (100) substrates under reversal of the polarization handedness condition. Under this condition, the pseudodielectric function is extremely sensitive to changes in the surrounding medium of the nanoparticle surface providing an excellent sensing platform competitive to conventional surface plasmon resonance. DNA sensing has been carried out by immobilizing a thiolated capture probe sequence from Helicobacter pylori

  20. A genetic variation map for chicken with 2.8 million single nucleotide polymorphisms

    Wong, G K; Hillier, L; Brandstrom, M; Croojmans, R; Ovcharenko, I; Gordon, L; Stubbs, L; Lucas, S; Glavina, T; Kaiser, P; Gunnarsson, U; Webber, C; Overton, I

    2005-02-20

    We describe a genetic variation map for the chicken genome containing 2.8 million single nucleotide polymorphisms (SNPs), based on a comparison of the sequences of 3 domestic chickens (broiler, layer, Silkie) to their wild ancestor Red Jungle Fowl (RJF). Subsequent experiments indicate that at least 90% are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about 5 SNP/kb for almost every possible comparison between RJF and domestic lines, between two different domestic lines, and within domestic lines--contrary to the idea that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated prior to domestication, and there is little to no evidence of selective sweeps for adaptive alleles on length scales of greater than 100 kb.