WorldWideScience

Sample records for adhd candidate gene

  1. Functional Insight From Fruit Flies on Human ADHD Candidate Genes

    Rohde, Palle Duun; Demontis, Ditte; Arvidson, Sandra Marie Neumann;

    2015-01-01

    of developing ADHD. We use Minos mutants, where target genes have been disrupted by the Minos transposable element, to test the effect on locomotor activity. By measuring the distance traveled, we find disparity in locomotor activity between control and Minos mutants. Impaired dopamine system...... underlies the majority of ADHD symptoms, and effective treatment is achieved with amphetamines. We fed flies with either 1.5 mg/ml dexamphetamine dissolved in 5% w/w sucrose or a 5% w/w sucrose solution. Treatment with dexamphetamine increased activity of controls and some Minos lines, and decreased...... activity levels for other mutants. Decreased activity level, when treated with dexamphetamine, is seen when using other ADHD animal models. Our findings suggest involvement of the proposed candidate genes Genes, Brain, and Behavior 2015 36 Talk Abstracts in hyperactivity in D. melanogaster, providing...

  2. ADHD Candidate Gene Study in a Population-Based Birth Cohort: Association with DBH and DRD2

    Nyman, Emma S.; Ogdie, Matthew N.; Loukola, Anu; Varilo, Teppo; Taanila, Anja; Hurtig, Tuula; Moilanen, Irma K.; Loo, Sandra K.; McGough, James J.; Jarvelin, Marjo-Riitta; Smalley, Susan L.

    2007-01-01

    A study aims to examine the genetic contribution if any to attention-deficit/hyperactivity disorder (ADHD). The results confirm the hypothesis and the association of dopamine [beta]-hydroxylase and dopamine receptor D2 genes with ADHD.

  3. Cognitive Functioning in Affected Sibling Pairs with ADHD: Familial Clustering and Dopamine Genes

    Loo, Sandra K.; Rich, Erika Carpenter; Ishii, Janeen; McGough, James; McCracken, James; Nelson, Stanley; Smalley, Susan L.

    2008-01-01

    Background: This paper examines familiality and candidate gene associations of cognitive measures as potential endophenotypes in attention-deficit/hyperactivity disorder (ADHD). Methods: The sample consists of 540 participants, aged 6 to 18, who were diagnosed with ADHD from 251 families recruited for a larger genetic study of ADHD. All members of…

  4. The Dopamine Receptor D4 Gene ("DRD4") Moderates Family Environmental Effects on ADHD

    Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Waldman, Irwin; Nigg, Joel T.

    2011-01-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a prime candidate for exploration of gene-by-environment interaction (i.e., G x E), particularly in relation to dopamine system genes, due to strong evidence that dopamine systems are dysregulated in the disorder. Using a G x E design, we examined whether the "DRD4" promoter 120-bp tandem repeat…

  5. A Candidate Gene Analysis of Methylphenidate Response in Attention-Deficit/Hyperactivity Disorder

    McGough, James J.; McCracken, James T.; Loo, Sandra K.; Manganiello, Marc; Leung, Michael C.; Tietjens, Jeremy R.; Trinh, Thao; Baweja, Shilpa; Suddath, Robert; Smalley, Susan L.; Hellemann, Gerhard; Sugar, Catherine A.

    2009-01-01

    Objective: This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). Method: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of…

  6. Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD.

    Arcos-Burgos, Mauricio; Muenke, Maximilian

    2010-11-01

    During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment protocols may take years to become routine clinical practice. However, when taken together, recent successes in genomics, pharmacogenomics, and genetic epidemiology have the potential (1) to prevent comorbid consequences of ADHD, (2) to individualize therapies for patients with ADHD, and (3) to define new epidemiological policies to aid with the impact of ADHD on society. Here, we present an overview of how genetic research may affect and improve the quality of life of patients with ADHD: as an example, we use the discovery of LPHN3, a new gene in which variants have recently been shown to be associated with ADHD. PMID:21432600

  7. Candidate gene prioritization with Endeavour.

    Tranchevent, Léon-Charles; Ardeshirdavani, Amin; ElShal, Sarah; Alcaide, Daniel; Aerts, Jan; Auboeuf, Didier; Moreau, Yves

    2016-07-01

    Genomic studies and high-throughput experiments often produce large lists of candidate genes among which only a small fraction are truly relevant to the disease, phenotype or biological process of interest. Gene prioritization tackles this problem by ranking candidate genes by profiling candidates across multiple genomic data sources and integrating this heterogeneous information into a global ranking. We describe an extended version of our gene prioritization method, Endeavour, now available for six species and integrating 75 data sources. The performance (Area Under the Curve) of Endeavour on cross-validation benchmarks using 'gold standard' gene sets varies from 88% (for human phenotypes) to 95% (for worm gene function). In addition, we have also validated our approach using a time-stamped benchmark derived from the Human Phenotype Ontology, which provides a setting close to prospective validation. With this benchmark, using 3854 novel gene-phenotype associations, we observe a performance of 82%. Altogether, our results indicate that this extended version of Endeavour efficiently prioritizes candidate genes. The Endeavour web server is freely available at https://endeavour.esat.kuleuven.be/. PMID:27131783

  8. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication.

    Arcos-Burgos, M; Jain, M; Acosta, M T; Shively, S; Stanescu, H; Wallis, D; Domené, S; Vélez, J I; Karkera, J D; Balog, J; Berg, K; Kleta, R; Gahl, W A; Roessler, E; Long, R; Lie, J; Pineda, D; Londoño, A C; Palacio, J D; Arbelaez, A; Lopera, F; Elia, J; Hakonarson, H; Johansson, S; Knappskog, P M; Haavik, J; Ribases, M; Cormand, B; Bayes, M; Casas, M; Ramos-Quiroga, J A; Hervas, A; Maher, B S; Faraone, S V; Seitz, C; Freitag, C M; Palmason, H; Meyer, J; Romanos, M; Walitza, S; Hemminger, U; Warnke, A; Romanos, J; Renner, T; Jacob, C; Lesch, K-P; Swanson, J; Vortmeyer, A; Bailey-Wilson, J E; Castellanos, F X; Muenke, M

    2010-11-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) has a very high heritability (0.8), suggesting that about 80% of phenotypic variance is due to genetic factors. We used the integration of statistical and functional approaches to discover a novel gene that contributes to ADHD. For our statistical approach, we started with a linkage study based on large multigenerational families in a population isolate, followed by fine mapping of targeted regions using a family-based design. Family- and population-based association studies in five samples from disparate regions of the world were used for replication. Brain imaging studies were performed to evaluate gene function. The linkage study discovered a genome region harbored in the Latrophilin 3 gene (LPHN3). In the world-wide samples (total n=6360, with 2627 ADHD cases and 2531 controls) statistical association of LPHN3 and ADHD was confirmed. Functional studies revealed that LPHN3 variants are expressed in key brain regions related to attention and activity, affect metabolism in neural circuits implicated in ADHD, and are associated with response to stimulant medication. Linkage and replicated association of ADHD with a novel non-candidate gene (LPHN3) provide new insights into the genetics, neurobiology, and treatment of ADHD. PMID:20157310

  9. ADHD

    ... be overly active. What are some of the signs of ADHD? Many children have trouble focusing and behaving at ... it is very important to get help for ADHD as early as possible. Additional Information: http: / / www. cdc. gov/ ...

  10. Correlation of a set of gene variants, life events and personality features on adult ADHD severity.

    Müller, Daniel J; Chiesa, Alberto; Mandelli, Laura; De Luca, Vincenzo; De Ronchi, Diana; Jain, Umesh; Serretti, Alessandro; Kennedy, James L

    2010-07-01

    Increasing evidence suggests that symptoms of attention deficit hyperactivity disorder (ADHD) could persist into adult life in a substantial proportion of cases. The aim of the present study was to investigate the impact of (1) adverse events, (2) personality traits and (3) genetic variants chosen on the basis of previous findings and (4) their possible interactions on adult ADHD severity. One hundred and ten individuals diagnosed with adult ADHD were evaluated for occurrence of adverse events in childhood and adulthood, and personality traits by the Temperament and Character Inventory (TCI). Common polymorphisms within a set of nine important candidate genes (SLC6A3, DBH, DRD4, DRD5, HTR2A, CHRNA7, BDNF, PRKG1 and TAAR9) were genotyped for each subject. Life events, personality traits and genetic variations were analyzed in relationship to severity of current symptoms, according to the Brown Attention Deficit Disorder Scale (BADDS). Genetic variations were not significantly associated with severity of ADHD symptoms. Life stressors displayed only a minor effect as compared to personality traits. Indeed, symptoms' severity was significantly correlated with the temperamental trait of Harm avoidance and the character trait of Self directedness. The results of the present work are in line with previous evidence of a significant correlation between some personality traits and adult ADHD. However, several limitations such as the small sample size and the exclusion of patients with other severe comorbid psychiatric disorders could have influenced the significance of present findings. PMID:20006992

  11. Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict

    Jernigan Katherine

    2010-04-01

    Full Text Available Abstract Background Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD; prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR on liability for ADHD. Method 304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution was genotyped and participants were assigned as having high (La/La N = 78, intermediate (La/Lg, La/short, N = 137, or low (Lg/Lg, Lg/short, short/short, N = 89 serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures. Results Hierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes. Conclusion Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to

  12. Psychiatric gene discoveries shape evidence on ADHD's biology.

    Thapar, A; Martin, J; Mick, E; Arias Vásquez, A; Langley, K; Scherer, S W; Schachar, R; Crosbie, J; Williams, N; Franke, B; Elia, J; Glessner, J; Hakonarson, H; Owen, M J; Faraone, S V; O'Donovan, M C; Holmans, P

    2016-09-01

    A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10(-4)) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders. PMID:26573769

  13. Psychiatric gene discoveries shape evidence on ADHD's biology

    Thapar, A; Martin, J; Mick, E; Arias Vásquez, A; Langley, K; Scherer, S W; Schachar, R; Crosbie, J; Williams, N; Franke, B; Elia, J; Glessner, J; Hakonarson, H; Owen, M J; Faraone, S V; O'Donovan, M C; Holmans, P

    2016-01-01

    A strong motivation for undertaking psychiatric gene discovery studies is to provide novel insights into unknown biology. Although attention-deficit hyperactivity disorder (ADHD) is highly heritable, and large, rare copy number variants (CNVs) contribute to risk, little is known about its pathogenesis and it remains commonly misunderstood. We assembled and pooled five ADHD and control CNV data sets from the United Kingdom, Ireland, United States of America, Northern Europe and Canada. Our aim was to test for enrichment of neurodevelopmental gene sets, implicated by recent exome-sequencing studies of (a) schizophrenia and (b) autism as a means of testing the hypothesis that common pathogenic mechanisms underlie ADHD and these other neurodevelopmental disorders. We also undertook hypothesis-free testing of all biological pathways. We observed significant enrichment of individual genes previously found to harbour schizophrenia de novo non-synonymous single-nucleotide variants (SNVs; P=5.4 × 10−4) and targets of the Fragile X mental retardation protein (P=0.0018). No enrichment was observed for activity-regulated cytoskeleton-associated protein (P=0.23) or N-methyl-D-aspartate receptor (P=0.74) post-synaptic signalling gene sets previously implicated in schizophrenia. Enrichment of ADHD CNV hits for genes impacted by autism de novo SNVs (P=0.019 for non-synonymous SNV genes) did not survive Bonferroni correction. Hypothesis-free testing yielded several highly significantly enriched biological pathways, including ion channel pathways. Enrichment findings were robust to multiple testing corrections and to sensitivity analyses that excluded the most significant sample. The findings reveal that CNVs in ADHD converge on biologically meaningful gene clusters, including ones now established as conferring risk of other neurodevelopmental disorders. PMID:26573769

  14. Is dopamine transporter gene effective on therapeutic response of methylphenidate in ADHD patients?

    Fatemeh Moharrari

    2015-01-01

    Full Text Available Attention-deficit/hyperactivity disorder (ADHD is the most common neuropsychiatric illness, which affects about 5% of children worldwide. An 80% genetic background is responsible for ADHD due to its appearance in familial relationships. In addition, dopamine regulation in synaptic spaces, which have a central role in development of ADHD, is moderated by dopamine transporter neurotransmitter, which in turn is modulated by dopamine transporter gene named SLC6A3 or DAT1. Methylphenidate as the first line and most important prescribed medication for ADHD blocks dopamine transporter and increases the dopamine concentration in synaptic clefts. In theory, methylphenidate relay to dopamine transporter to play a role, and dopamine transporter synthesis is dependent on DAT1. This gene have 40 base pair in its 3`-untranslated region end that repeat from 3 to 11 times, with most frequent 9 and 10 repeats in human, forming several alleles in carriers including 9R and 10R and genotypes including 9R/9R, 10R/10R, 9R/10R. These genotypes, as the first suspected candidates, may explain why methylphenidate therapy is not sufficient some patients and how the side effects appear in some cases and not in all patients. Many studies have performed to investigate the association between responses to methylphenidate and genotypes and yet no consistency has occurred. This article has a rapid review on concerned literature.

  15. ADHD

    ... been a problem. Schools can also play a part in helping students with ADHD. Most schools will develop a plan ... they head off to college or start a job. When the time comes for you to do this, you may ...

  16. Testing candidate genes for attention-deficit/hyperactivity disorder in fruit flies using a high throughput assay for complex behavior

    Rohde, Palle Duun; Madsen, Lisbeth Strøm; Arvidson, Sandra Marie Neumann; Loeschcke, Volker; Demontis, Ditte; Kristensen, Torsten Nygaard

    2016-01-01

    Fruit flies are important model organisms for functional testing of candidate genes in multiple disciplines, including the study of human diseases. Here we use a high-throughput locomotor activity assay to test the response on activity behavior of gene disruption in Drosophila melanogaster. The aim...... behavioral activity in fruit flies. Results provide additional support for the investigated genes being risk candidate genes for ADHD in humans....

  17. Cattle Candidate Genes for Milk Production Traits

    Kadlec,Tomáš

    2012-01-01

    The aim of this thesis is to make an overview of important candidate genes affecting milk yield and milk quality parameters, with an emphasis on genes associated with the quantity and quality of milk proteins and milk fat.

  18. Evaluating historical candidate genes for schizophrenia

    Farrell, M S; Werge, T; Sklar, P;

    2015-01-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these...... genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these...... genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why...

  19. Candidate genes for behavioural ecology

    Fitzpatrick, M.J.; Ben-Sahar, Y.; Smid, H.M.; Vet, L.E.M.; Robinson, G.E.; Sokolowski, M.B.

    2005-01-01

    In spite of millions of years of evolutionary divergence, the conservation of gene function is common across distant lineages. As such, genes that are known to influence behaviour in one organism are likely to influence similar behaviours in other organisms. Recent studies of the evolution of behavi

  20. Alcoholism and Alternative Splicing of Candidate Genes

    Toshikazu Sasabe; Shoichi Ishiura

    2010-01-01

    Gene expression studies have shown that expression patterns of several genes have changed during the development of alcoholism. Gene expression is regulated not only at the level of transcription but also through alternative splicing of pre-mRNA. In this review, we discuss some of the evidence suggesting that alternative splicing of candidate genes such as DRD2 (encoding dopamine D2 receptor) may form the basis of the mechanisms underlying the pathophysiology of alcoholism. These reports sugg...

  1. Evaluating historical candidate genes for schizophrenia.

    Farrell, M S; Werge, T; Sklar, P; Owen, M J; Ophoff, R A; O'Donovan, M C; Corvin, A; Cichon, S; Sullivan, P F

    2015-05-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia. PMID:25754081

  2. Converging evidence does not support GIT1 as an ADHD risk gene

    Klein, M.; Van der Vloet, M.; Harich, B.; Van Hulzen, K.; Onnink, A.; Hoogman, M.; Guadalupe, T.; Zwiers, M.; Groothuismink, J.; Verberkt, A.; Nijhof, B.; Castells-Nobau, A.; Faraone, S; Buitelaar, J.; Schenck, A

    2015-01-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric G...

  3. Cattle Candidate Genes for Meat Production Traits

    Bláhová, Alice

    2013-01-01

    The objective of this study was to compile a summary of the most important candidate genes for meat production. The studied genes were: GH, GHR, MSTN, MyoD family, leptin, IGF, TG5, SCD, DGAT and STAT5A. Growth hormone (GH) is involved in physiological processes of growth and metabolism. Growth hormone receptor (GHR) has been proposed as a candidate gene for meat production in cattle. Myostatin is a significant marker. It affects the amount of muscle, reduces marbling and elevate meat tendern...

  4. Is dopamine transporter gene effective on therapeutic response of methylphenidate in ADHD patients?

    Fatemeh Moharrari; Soheila Barabadian

    2015-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric illness, which affects about 5% of children worldwide. An 80% genetic background is responsible for ADHD due to its appearance in familial relationships. In addition, dopamine regulation in synaptic spaces, which have a central role in development of ADHD, is moderated by dopamine transporter neurotransmitter, which in turn is modulated by dopamine transporter gene named SLC6A3 or DAT1. Methylphenidate as the ...

  5. Toward a better understanding of ADHD: LPHN3 gene variants and the susceptibility to develop ADHD

    Arcos-Burgos, Mauricio; Muenke, Maximilian

    2010-01-01

    During the past 15 years, an impressive amount of genetic information has become available in the research field of psychiatry, particularly as it relates to attention-deficit/hyperactivity disorder (ADHD). However, the classical clinical approach to ADHD has minimally affected and not significantly been improved by this genetic revolution. It is difficult to predict how long it will take for genetic findings to alter the way clinicians treat patients with ADHD. New medications or treatment p...

  6. Folate metabolism gene 5,10-methylenetetrahydrofolate reductase (MTHFR is associated with ADHD in myelomeningocele patients.

    Catherine J Spellicy

    Full Text Available The objective of this study was to examine the relation between the 5, 10-methylenetetrahydrofolate reductase (MTHFR gene and behaviors related to attention- deficit/hyperactivity disorder (ADHD in individuals with myelomeningocele. The rationale for the study was twofold: folate metabolizing genes, (e.g. MTHFR, are important not only in the etiology of neural tube defects but are also critical to cognitive function; and individuals with myelomeningocele have an elevated incidence of ADHD. Here, we tested 478 individuals with myelomeningocele for attention-deficit hyperactivity disorder behavior using the Swanson Nolan Achenbach Pelham-IV ADHD rating scale. Myelomeningocele participants in this group for whom DNAs were available were genotyped for seven single nucleotide polymorphisms (SNPs in the MTHFR gene. The SNPs were evaluated for an association with manifestation of the ADHD phenotype in children with myelomeningocele. The data show that 28.7% of myelomeningocele participants exhibit rating scale elevations consistent with ADHD; of these 70.1% had scores consistent with the predominantly inattentive subtype. In addition, we also show a positive association between the SNP rs4846049 in the 3'-untranslated region of the MTHFR gene and the attention-deficit hyperactivity disorder phenotype in myelomeningocele participants. These results lend further support to the finding that behavior related to ADHD is more prevalent in patients with myelomeningocele than in the general population. These data also indicate the potential importance of the MTHFR gene in the etiology of the ADHD phenotype.

  7. Candidate gene effects on beef quality

    Ekerljung, Marie

    2012-01-01

    The contribution of five candidate genes to the variation in meat tenderness, pH, colour, marbling and water holding capacity (WHC) was analysed in muscle samples from 243 young bulls of Angus, Charolais, Hereford, Limousin, or Simmental breed, raised in Swedish commercial herds. The animals were genotyped for single nucleotide polymorphisms (SNPs) in the genes encoding calpain 1 (CAPN1:c.947G>C), calpastatin, (CAST:c.155C>T), diacylglycerol O-acyltransferase 1 (DGAT1), leptin (UASMS2C>T) a...

  8. The ATXN1 and TRIM31 genes are related to intelligence in an ADHD background: Evidence from a large collaborative study totaling 4,963 Subjects

    Rizzi, Thais S; Arias-Vasquez, Alejandro; Rommelse, Nanda; Kuntsi, Jonna; Anney, Richard; Asherson, Philip; Buitelaar, Jan; Banaschewski, Tobias; Ebstein, Richard; Ruano, Dina; Van der Sluis, Sophie; Markunas, Christina A; Garrett, Melanie E; Ashley-Koch, Allison E; Kollins, Scott H; Anastopoulos, Arthur D; Hansell, Narelle K; Wright, Margaret J; Montgomery, Grant W; Martin, Nicholas G; Harris, Sarah E; Davies, Gail; Tenesa, Albert; Porteous, David J; Starr, John M; Deary, Ian J; St. Pourcain, Beate; Smith, George Davey; Timpson, Nicholas J; Evans, David M; Gill, Michael; Miranda, Ana; Mulas, Fernando; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Sonuga-Barke, Edmund; Steinhausen, Hans Christoph; Taylor, Eric; Faraone, Stephen V; Franke, Barbara; Posthuma, Danielle

    2011-01-01

    Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and 29451 SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder. © 2010 Wiley-Liss, Inc. PMID:21302343

  9. Collaborative Analysis of DRD4 and DAT Genotypes in Population-Defined ADHD Subtypes

    Todd, Richard D.; Huang, Hongyan; Smalley, Susan L.; Nelson, Stanley F.; Willcutt, Erik G.; Pennington, Bruce F.; Smith, Shelley D.; Faraone, Stephen V.; Neuman, Rosalind J.

    2005-01-01

    Background: It has been proposed that some of the variability in reporting of associations between attention deficit hyperactivity disorder (ADHD) and candidate genes may result from mixing of genetically heterogeneous forms of ADHD using DSM-IV criteria. The goal of the current study is to test whether population-based ADHD subtypes defined by…

  10. Deletions and candidate genes in Williams syndrome

    Perez Jurado, L.A.; Peoples, R.; Francke, U. [Stanford Univ. CA (United States)] [and others

    1994-09-01

    Hemizygosity at the elastin locus (ELN) on chromosome 7q11.23 has recently been reported in several familial and sporadic cases of the developmental disorder, Williams syndrome (WS). Because the deletion is greater than the span of the ELN gene, a contiguous gene deletion syndrome has been suggested as the probable molecular basis for this condition. Thus far, neither the size of the deletion(s), nor other genes within it are known. We have analyzed samples from 27 sporadic WS patients by genotyping two multiallelic ELN intragenic polymorphisms, detectable by PCR amplification, and by Southern blotting for ELN gene dosage. Twenty four patients were hemizygous at the ELN locus while 3 showed no deletion or detectable rearrangement. Genotype studies on parental DNA were informative in 12 of the deletions. All 12 were due to de novo events, 8 in the maternal and 4 in the paternal chromosome. In an attempt to identify genes involved in WS we are also using a candidate gene approach. Delayed clearance of an exogenous calcium load with normal or slightly increased calcitonin levels in serum has been documented in WS patients suggesting a defective calcitonin action or calcium sensing function. The calcitonin receptor (CTR) gene is, therefore, a good candidate since CTR has a dual role as a hormonal receptor for calcitonin and an extracellular calcium sensor. We have mapped the CTR gene to chromosome 7q21.1 by PCR-SSCA of somatic cell hybrids and FISH analysis. Using two color FISH with probes for ELN and CTR, both loci are located on 7q at a distance of {approximately}10 Mb, CTR being telomeric. Our CTR probe does not detect any genomic abnormality by FISH or Southern blot in the patients` samples analyzed. We have identified a diallelic polymorphism in the CTR cDNA and are currently testing the hypothesis of an impaired CTR expression as responsible for some of the clinical features of WS by analysing the CTR transcripts by RT-PCR.

  11. CRISPLD2: a novel NSCLP candidate gene.

    Chiquet, Brett T; Lidral, Andrew C; Stal, Samuel; Mulliken, John B; Moreno, Lina M; Arcos-Burgos, Mauricio; Arco-Burgos, Mauricio; Valencia-Ramirez, Consuelo; Blanton, Susan H; Hecht, Jacqueline T

    2007-09-15

    Non-syndromic cleft lip with or without cleft palate (NSCLP) results from the complex interaction between genes and environmental factors. Candidate gene analysis and genome scans have been employed to identify the genes contributing to NSCLP. In this study, we evaluated the 16q24.1 chromosomal region, which has been identified by multiple genome scans as an NSCLP region of interest. Two candidate genes were found in the region: interferon regulatory factor 8 (IRF8) and cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2). Initially, Caucasian and Hispanic NSCLP multiplex families and simplex parent-child trios were genotyped for single nucleotide polymorphisms (SNPs) in both IRF8 and CRISPLD2. CRISPLD2 was subsequently genotyped in a data set comprised of NSCLP families from Colombia, South America. Linkage disequilibrium analysis identified a significant association between CRISPLD2 and NSCLP in both our Caucasian and Hispanic NSCLP cohorts. SNP rs1546124 and haplotypes between rs1546124 and either rs4783099 or rs16974880 were significant in the Caucasian multiplex population (P=0.01, P=0.002 and P=0.001, respectively). An altered transmission of CRISPLD2 SNPs rs8061351 (P=0.02) and rs2326398 (P=0.06) was detected in the Hispanic population. No association was found between CRISPLD2 and our Colombian population or IRF8 and NSCLP. In situ hybridization showed that CRISPLD2 is expressed in the mandible, palate and nasopharynx regions during craniofacial development at E13.5-E17.5, respectively. Altogether, these data suggest that genetic variation in CRISPLD2 has a role in the etiology of NSCLP. PMID:17616516

  12. An interaction between a polymorphism of the serotonin transporter (5HTT gene and the clinical picture of adolescents with combined type of ADHD (hyperkinetic disorder and youth drinking

    Gorzkowska, Izabela

    2014-06-01

    Full Text Available Introduction: The combined type of ADHD and alcohol dependence are two different disorders. Research demonstrate that 45-55% of patients diagnosed with ADHD also suffer from comorbid substance abuse, and 11-55% of patients diagnosed with substance abuse suffer from undiagnosed ADHD. Alcohol is by far the most widely used psychoactive substance in the European culture. The serotonin transporter (5HHT gene has been implicated as one of the candidate genes in both disorders in recent molecular genetic research. Aim: The aim of the present study was to seek a common clinical and biological marker for hyperkinetic disorder and youth drinking. Methods: The study was conducted between 2008 and 2012. The sample consisted of 100 combined type ADHD patients: 51 adolescents youth drinking and 100 individuals without mental disorders or addiction in a population-based group. The 5HHT gene polymorphism was examined using PCR (Polymerase Chain Reaction. Statistical analysis was conducted with STATISTICA.PL software (version 5.0.97 licensed by StatSoft, Inc. USA. Results: A preferential trend for the “s” short allele of the investigated 5HHT gene polymorphism was observed in all the groups of adolescents compared to the population-based group of adults without alcohol dependence (p=0.01. Conclusion: Based on the conducted study a provisional conclusion may be drawn that the presence of the short “s” allele of the 5HTT gene polymorphism may be a prognostic factor of impulsivity in ADHD and of predisposition to alcohol dependence.

  13. Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function.

    Fliers, E.A.; Arias Vasquez, A.; Poelmans, G.J.V.; Rommelse, N.N.; Altink, M.E.; Buschgens, C.J.M.; Asherson, P.; Banaschewski, T.; Ebstein, R.; Gill, M.; Miranda, A.; Mulas, F.; Oades, R.D.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Sonuga-Barke, E.S.J.; Steinhausen, H.C.; Faraone, S.V.; Buitelaar, J.K.; Franke, B.

    2012-01-01

    OBJECTIVES: Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD ma

  14. Unifying Candidate Gene and GWAS Approaches in Asthma

    Michel, Sven; Liang, Liming; Depner, Martin; Klopp, Norman; Ruether, Andreas; Kumar, Ashish; Schedel, Michaela; Vogelberg, Christian; Mutius, Erika von; Berg, Andrea von; Bufe, Albrecht; Rietschel, Ernst; Heinzmann, Andrea; Laub, Otto; Simma, Burkhard

    2010-01-01

    The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children....

  15. Catecholaminergic Gene Variants: Contribution in ADHD and Associated Comorbid Attributes in the Eastern Indian Probands

    Paramita Ghosh

    2013-01-01

    Full Text Available Contribution of genes in attention deficit hyperactivity disorder (ADHD has been explored in various populations, and several genes were speculated to contribute small but additive effects. We have assessed variants in four genes, DDC (rs3837091 and rs3735273, DRD2 (rs1800496, rs1801028, and rs1799732, DRD4 (rs4646984 and rs4646983, and COMT (rs165599 and rs740603 in Indian ADHD subjects with comorbid attributes. Cases were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV-TR after obtaining informed written consent. DNA isolated from peripheral blood leukocytes of ADHD probands (N=170, their parents (N=310, and ethnically matched controls (n=180 was used for genotyping followed by population- and family-based analyses by the UNPHASED program. DRD4 sites showed significant difference in allelic frequencies by case-control analysis, while DDC and COMT exhibited bias in familial transmission (P<0.05. rs3837091 “AGAG,” rs3735273 “A,” rs1799732 “C,” rs740603 “G,” rs165599 “G” and single repeat alleles of rs4646984/rs4646983 showed positive correlation with co-morbid characteristics (P<0.05. Multi dimensionality reduction analysis of case-control data revealed significant interactive effects of all four genes (P<0.001, while family-based data showed interaction between DDC and DRD2 (P=0.04. This first study on these gene variants in Indo-Caucasoid ADHD probands and associated co-morbid conditions indicates altered dopaminergic neurotransmission in ADHD.

  16. Evaluating gene × gene and gene × smoking interaction in rheumatoid arthritis using candidate genes in GAW15

    Mei Ling; Li Xiaohui; Yang Kai; Cui Jinrui; Fang Belle; Guo Xiuqing; Rotter Jerome I

    2007-01-01

    Abstract We examined the potential gene × gene interactions and gene × smoking interactions in rheumatoid arthritis (RA) using the candidate gene data sets provided by Genetic Analysis Workshop 15 Problem 2. The multifactor dimensionality reduction (MDR) method was used to test gene × gene interactions among candidate genes. The case-only sample was used to test gene × smoking interactions. The best predictive model was the single-locus model with single-nucleotide polymorphism (SNP) rs247660...

  17. The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development.

    Lange, M; Norton, W; Coolen, M; Chaminade, M; Merker, S; Proft, F; Schmitt, A; Vernier, P; Lesch, K-P; Bally-Cuif, L

    2012-09-01

    Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. PMID:22508465

  18. The Important Candidate Genes in Goats - A Review

    China SUPAKORN

    2009-01-01

    Full Text Available A total of 271 candidate genes have been detected in goats. However, comprehensive investigations have been carried out on the polymorphism of some genes, involved in the control of economic traits. Candidate genes have an effect on the physiological pathway, metabolism and expression of phenotypes. For growth traits, growth hormone (GH, growth hormone receptor (GHR, insulin like growth factor I (IGF-I, leptin (LEP, caprine pituitary specific transcription factor-1 (POU1F1, caprine myostatin (MSTN and bone morphogenetic protein (BMP genes are necessary for bone formation, birth weight, weaning weight, body condition and muscle growth. For reproduction, forkhead box L 2 (FOXL2, melatonin receptor 1A (MTNR1A, sex determination region of Y chromosome (SRY and amelogenin (AMEL genes influence sex determination and proliferation. The major candidate genes for milk yield and milk composition traits are the casein gene and their family. Keratin associated protein (KAP and melanocortin 1 receptor (MC1R genes are candidate genes for wool traits. The major histocompatibility complex (MHC gene is considered important for the immune system and disease resistance traits. The functions of these genes on economically important traits are different. Some genes have synergistic or antagonistic effects in nature for expression of phenotypic traits. On the other hand, some genes could control more than one trait. Also, the producers should be concerned with these effects because selection of a single trait by using only a gene could affect other traits. Therefore, the identification of candidate genes and their mutations which cause variations of gene expression and phenotype of economic traits will help breeders to search some genetic markers for these economic traits. It may be used as an aid in the selection of parent stock at an early age in the future.

  19. Dopamine Transporter Gene Moderates Response to Behavioral Parent Training in Children With ADHD: A Pilot Study

    van den Hoofdakker, Barbara J.; Nauta, Maaike H.; Dijck-Brouwer, D. A. Janneke; van der Veen-Mulders, Lianne; Sytema, Sjoerd; Emmelkamp, Paul M.G.; Minderaa, Ruud B.; Hoekstra, Pieter J.

    2012-01-01

    There is great variability in the degree to which children with attention deficit/hyperactivity disorder (ADHD) improve through behavioral treatments. This study investigates the influence of the dopamine transporter gene (SCL6A3/DAT1) on outcome of behavioral parent training (BPT). Study subjects were a subsample (n = 50, for whom DAT1 genotypes were available) of a randomized controlled BPT effectiveness study (N = 94) comparing BPT plus ongoing routine clinical care (RCC) versus RCC alone ...

  20. ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila.

    van der Voet, M; Harich, B; Franke, B; Schenck, A

    2016-04-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. Here we report a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options. PMID:25962619

  1. Unifying candidate gene and GWAS Approaches in Asthma.

    Sven Michel

    Full Text Available The first genome wide association study (GWAS for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing. Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a GWAS coverage is insufficient for many asthma candidate genes, (b imputation based on these data is reliable but incomplete, and (c SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.

  2. Intraindividual variability (IIV) in an animal model of ADHD - the Spontaneously Hypertensive Rat

    Sagvolden Terje; Perry Guy ML; Faraone Stephen V

    2010-01-01

    Abstract Attention-deficit/hyperactivity disorder (ADHD) is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV) in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously ...

  3. A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137

    Devanna, Paolo; Vernes, Sonja C.

    2014-02-01

    Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes.

  4. Shared Genetic Influences on ADHD Symptoms and Very Low-Frequency EEG Activity: A Twin Study

    Tye, Charlotte; Rijsdijk, Fruhling; Greven, Corina U.; Kuntsi, Jonna; Asherson, Philip; McLoughlin, Grainne

    2012-01-01

    Background: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex aetiology. The identification of candidate intermediate phenotypes that are both heritable and genetically linked to ADHD may facilitate the detection of susceptibility genes and elucidate aetiological pathways.…

  5. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    Hansen, Niclas Tue; Brunak, Søren; Altman, R. B.

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge, bu...

  6. Candidate gene studies in human anxiety disorders

    Donner, Jonas

    2012-01-01

    Anxiety disorders, such as panic disorder (PD), obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, and phobias are common psychiatric disorders, characterized by exaggerated, prolonged and debilitating levels of anxiety. They are complex diseases with onset influenced by both environmental and genetic factors, but so far little progress has been made in identifying solid susceptibility genes. The aim of this study was to shed light on the genetic basi...

  7. Association of dopamine transporter gene variants with childhood ADHD features in bipolar disorder.

    Greenwood, Tiffany A; Joo, Eun-Jeong; Shekhtman, Tatyana; Sadovnick, A Dessa; Remick, Ronald A; Keck, Paul E; McElroy, Susan L; Kelsoe, John R

    2013-03-01

    Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (P = 0.007) and for variants in introns 9 and 13 with mood instability (P = 0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (P = 0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity and mood instability (P = 0.002, 0.007, and 8 × 10(-4), respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits. PMID:23255304

  8. Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

    Sigurdardottir, Helen L.; Kranz, Georg S.; Rami‐Mark, Christina; James, Gregory M.; Vanicek, Thomas; Gryglewski, Gregor; Kautzky, Alexander; Hienert, Marius; Traub‐Weidinger, Tatjana; Mitterhauser, Markus; Wadsak, Wolfgang; Hacker, Marcus; Rujescu, Dan; Kasper, Siegfried

    2016-01-01

    Abstract Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. PMID:26678348

  9. Oligonucleotide conjugates - Candidates for gene silencing therapeutics.

    Gooding, Matt; Malhotra, Meenakshi; Evans, James C; Darcy, Raphael; O'Driscoll, Caitriona M

    2016-10-01

    The potential therapeutic and diagnostic applications of oligonucleotides (ONs) have attracted great attention in recent years. The capability of ONs to selectively inhibit target genes through antisense and RNA interference mechanisms, without causing un-intended sideeffects has led them to be investigated for various biomedical applications, especially for the treatment of viral diseases and cancer. In recent years, many researchers have focused on enhancing the stability and target specificity of ONs by encapsulating/complexing them with polymers or lipid chains to formulate nanoparticles/nanocomplexes/micelles. Also, chemical modification of nucleic acids has emerged as an alternative to impart stability to ONs against nucleases and other degrading enzymes and proteins found in blood. In addition to chemically modifying the nucleic acids directly, another strategy that has emerged, involves conjugating polymers/peptide/aptamers/antibodies/proteins, preferably to the sense strand (3'end) of siRNAs. Conjugation to the siRNA not only enhances the stability and targeting specificity of the siRNA, but also allows for the development of self-administering siRNA formulations, with a much smaller size than what is usually observed for nanoparticle (∼200nm). This review concentrates mainly on approaches and studies involving ON-conjugates for biomedical applications. PMID:27521696

  10. Candidate genes of idiopathic pulmonary fibrosis: current evidence and research

    Zhou W

    2016-02-01

    Full Text Available Wei Zhou,1,2 Yaping Wang1,2 1Department of Medical Genetics, 2Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, People's Republic of China Abstract: Idiopathic pulmonary fibrosis (IPF is a group of common and lethal forms of idiopathic interstitial pulmonary disease. IPF is characterized by a progressive decline in lung function with a median survival of 2–3 years after diagnosis. Although the pathogenesis of the disease remains unknown, genetic predisposition could play a causal role in IPF. A set of genes have been identified as candidate genes of IPF in the past 20 years. However, the recent technological advances that allow for the analysis of millions of polymorphisms in different subjects have deepened the understanding of the genetic complexity of IPF susceptibility. Genome-wide association studies and whole-genome sequencing continue to reveal the genetic loci associated with IPF risk. In this review, we describe candidate genes on the basis of their functions and aim to gain a better understanding of the genetic basis of IPF. The discovered candidate genes may help to clarify pivotal aspects in the diagnosis, prognosis, and therapies of IPF. Keywords: idiopathic pulmonary fibrosis, candidate genes, susceptibility 

  11. A functional variant of the serotonin transporter gene (SLC6A4) moderates impulsive choice in ADHD boys and siblings

    Sonuga-Barke, Edmund J. S.; Kumsta, Robert; Schlotz, Wolff; Lasky-Su, Jessica; Marco, Rafaela; Miranda, Ana; Mulas, Fernando; Oades, Robert D.; Banaschewski, Tobias; Mueller, Ueli; Andreou, Penny; Christiansen, Hanna; Gabriels, Isabel; Uebel, Henrik; Kuntsi, Jonna; Franke, Barbara; Buitelaar, Jan; Ebstein, Richard; Gill, Michael; Anney, Richard; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Asherson, Philip; Faraone, Stephen V.

    2011-01-01

    Background Impulsive drive for immediate reward (IDIR) and delay aversion are dissociable elements of the preference for immediate over delayed rewards seen in Attention Deficit/Hyperactivity Disorder (ADHD). We hypothesized that IDIR would be associated with dopamine regulating genes and delay aversion with serotonin regulating genes. Methods IDIR and delay aversion were measured in 459 male children and adolescents (328 ADHD and 131 unaffected siblings) using a laboratory choice task. The sample was genotyped for the 5HTT (SLC6A4) promoter 5-HTTLPR polymorphism and a DAT1 (SLC6A3) 40-base pair VNTR located in the 3`-untranslated region of the gene. Results There was no effect of DAT1 on IDIR. As predicted 5-HTTLPR s-allele carriers were more delay averse. This effect was driven by the s/l genotype in the ADHD group. These results were not altered by taking account of the rs25531 A/G SNP and were independent of age, IQ and ODD symptoms. Conclusions The results support the genetic distinctiveness of IDIR and delay aversion in ADHD and implicate serotonin function in delay aversion. Possible explanations of the heterosis effect in the ADHD cases are presented. PMID:21497794

  12. Identification of candidate genes for dyslexia susceptibility on chromosome 18.

    Thomas S Scerri

    Full Text Available Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s conferring susceptibility by a two stage strategy of linkage and association analysis.Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R, dymeclin (DYM and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L.Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

  13. Reranking candidate gene models with cross-species comparison for improved gene prediction

    Pereira Fernando CN

    2008-10-01

    Full Text Available Abstract Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc. Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models.

  14. Are TMEM genes potential candidate genes for panic disorder?

    Gregersen, Noomi O; Buttenschøn, Henriette Nørmølle; Hedemand, Anne;

    2014-01-01

    We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12, a...

  15. CANDIDATE GENE ANALYSIS IN ISRAELI SOLDIERS WITH STRESS FRACTURES

    Ran Yanovich

    2012-03-01

    Full Text Available To investigate the association of polymorphisms within candidate genes which we hypothesized may contribute to stress fracture predisposition, a case-control, cross- sectional study design was employed. Genotyping 268 Single Nucleotide Polymorphisms- SNPs within 17 genes in 385 Israeli young male and female recruits (182 with and 203 without stress fractures. Twenty-five polymorphisms within 9 genes (NR3C1, ANKH, VDR, ROR2, CALCR, IL6, COL1A2, CBG, and LRP4 showed statistically significant differences (p < 0.05 in the distribution between stress fracture cases and non stress fracture controls. Seventeen genetic variants were associated with an increased stress fracture risk, and eight variants with a decreased stress fracture risk. None of the SNP associations remained significant after correcting for multiple comparisons (false discovery rate- FDR. Our findings suggest that genes may be involved in stress fracture pathogenesis. Specifically, the CALCR and the VDR genes are intriguing candidates. The putative involvement of these genes in stress fracture predisposition requires analysis of more cases and controls and sequencing the relevant genomic regions, in order to define the specific gene mutations

  16. No Evidence for Association between Amelogenesis Imperfecta and Candidate Genes

    M Ghandehari Motlagh

    2009-03-01

    Full Text Available "nBackground: Amelogenesis imperfecta (AI is an inherited tooth disorder. Despite the fact that up to now, several gene muta­tions in MMP20, ENAM, AMELX and KLK4 genes have been reported to be associated with AI, many other genes sug­gested to be involved. The main objective of this study was to find the mutations in three major candidate genes including MMP20, ENAM and KLK4 responsible for AI from three Iranian families with generalized hypoplastic phenotype in all teeth. "nMethods: All exon/intron boundaries of subjected genes were amplified by polymerase chain reaction and subjected to direct sequencing."nResults: One polymorphisms was identified in KLK4 exon 2, in one family a homozygous mutation was found in the third base of codon 22 for serine (TCG>TCT, but not in other families. Although these base substitutions have been occurred in the signaling domain, they do not seem to influence the activity of KLK4 protein."nConclusion: Our results might support the further evidence for genetic heterogeneity; at least, in some AI cases are not caused by a gene in these reported candidate genes.

  17. ADHD Medications

    ... How Can I Help a Friend Who Cuts? ADHD Medicines KidsHealth > For Teens > ADHD Medicines Print A ... Medicación para el tratamiento del TDAH (ADHD) Managing ADHD With Medicine Just about everyone has trouble concentrating ...

  18. Causative Factors for ADHD: Role of Copy Number Variants in ADHD

    J Gordon Millichap; John J Millichap

    2014-01-01

    Investigators from Brazil determined if copy number variants (CNVs) in glutamate metabotropic receptor genes (GRM) were overrepresented in 1038 individuals with ADHD compared to 1057 subjects without ADHD.

  19. Moderator Effects of Working Memory on the Stability of ADHD Symptoms by Dopamine Receptor Gene Polymorphisms during Development

    Trampush, Joey W.; Jacobs, Michelle M.; Hurd, Yasmin L.; Newcorn, Jeffrey H.; Halperin, Jeffrey M.

    2014-01-01

    We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance…

  20. Absence of linkage of apparently single gene mediated ADHD with the human syntenic region of the mouse mutant coloboma

    Hess, E.J.; Rogan, P.K.; Domoto, M. [Pennsylvania State Univ. College of Medicine, Hershey, PA (United States)] [and others

    1995-12-18

    Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11-p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval. 39 refs., 2 figs., 1 tab.

  1. COMT Val[superscript 108/158] Met Gene Variant, Birth Weight, and Conduct Disorder in Children with ADHD

    Sengupta, Sarojini M.; Grizenko, Natalie; Schmitz, Norbert; Schwartz, George; Amor, Leila Ben; Bellingham, Johanne; de Guzman, Rosherrie; Polotskaia, Anna; Stepanian, Marina Ter; Thakur, Geeta; Joober, Ridha

    2006-01-01

    Objective: In a recent study, Thapar and colleagues reported that COMT "gene variant and birth weight predict early-onset antisocial behavior in children" with attention-deficit/hyperactivity disorder. We have attempted to replicate these findings in a group of ADHD children using a similar research design. Method: Children (n = 191) between 6 and…

  2. Lack of Association between a 3'UTR VNTR Polymorphism of Dopamine Transporter Gene (SLC6A3) and ADHD in a Brazilian Sample of Adult Patients

    Aperecida da Silva, Maria; Cordeiro, Quirino; Louza, Mario; Vallada, Homero

    2011-01-01

    Objective: To investigate a possible association between a 3'UTR VNTR polymorphism of the dopamine transporter gene (SLC6A3) and ADHD in a Brazilian sample of adult patients. Method: Study Case-control with 102 ADHD adult outpatients ("DSM-IV" criteria) and 479 healthy controls. The primers' sequence used were: 3'UTR-Forward: 5' TGT GGT GAT GGG…

  3. The Dopamine Receptor D4 7-Repeat Allele and Prenatal Smoking in ADHD-Affected Children and Their Unaffected Siblings: No Gene-Environment Interaction

    Altink, Marieke E.; Arias-Vasquez, Alejandro; Franke, Barbara; Slaats-Willemse, Dorine I. E.; Buschgens, Cathelijne J. M.; Rommelse, Nanda N. J.; Fliers, Ellen A.; Anney, Richard; Brookes, Keeley-Joanne; Chen, Wai; Gill, Michael; Mulligan, Aisling; Sonuga-Barke, Edmund; Thompson, Margaret; Sergeant, Joseph A.; Faraone, Stephen V.; Asherson, Philip; Buitelaar, Jan K.

    2008-01-01

    Background: The dopamine receptor D4 ("DRD4") 7-repeat allele and maternal smoking during pregnancy are both considered as risk factors in the aetiology of attention deficit hyperactivity disorder (ADHD), but few studies have been conducted on their interactive effects in causing ADHD. The purpose of this study is to examine the gene by…

  4. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S;

    2011-01-01

    The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere...... as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a...

  5. Slitrks as emerging candidate genes involved in neuropsychiatric disorders

    Proenca, Catia C.; Gao, Kate P.; Shmelkov, Sergey V.; Rafii, Shahin; Lee, Francis S

    2011-01-01

    Slitrks are a family of structurally-related transmembrane proteins belonging to the leucine-rich repeat (LRR) superfamily. Six family members exist (Slitrk1–Slitrk6), and all are highly expressed in the central nervous system (CNS). Slitrks have been implicated in mediating basic neuronal processes ranging from neurite outgrowth and dendritic elaboration to neuronal survival. Recent studies in humans and genetic mouse models have led to the identification of Slitrks as candidate genes that m...

  6. Genetics of intracerebral hemorrhage: Insights from candidate gene approaches

    Baoqiong Liu; Le Zhang; Qidong Yang

    2012-01-01

    Intracerebral hemorrhage (ICH) is a heterogeneous disease with genetic factors playing an important role. Association studies on a wide range of candidate pathways suggest a weak but significant effect for several alleles with ICH risk. Among the most widely investigated genes are those involved in the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme), coagulation pathway (e.g., Factor XIII, Factor VII, platelet-activating factor acetylhydrolase, Factor V Leiden, and ...

  7. Association of candidate genes with antisocial drug dependence in adolescents

    Corley, Robin P.; Zeiger, Joanna S.; Crowley, Thomas; Ehringer, Marissa A.; Hewitt, John K.; Christian J Hopfer; Lessem, Jeffrey; McQueen, Matthew B.; Rhee, Soo Hyun; Smolen, Andrew; Stallings, Michael C.; Young, Susan E.; Krauter, Kenneth

    2008-01-01

    The Colorado Center for Antisocial Drug Dependence (CADD) is using several research designs and strategies in its study of the genetic basis for antisocial drug dependence in adolescents. This study reports Single Nucleotide Polymorphism (SNP) association results from a Targeted Gene Assay (SNP chip) of 231 Caucasian male probands in treatment with antisocial drug dependence and a matched set of community controls. The SNP chip was designed to assay 1500 SNPs distributed across 50 candidate g...

  8. Annual Killifish Transcriptomics and Candidate Genes for Metazoan Diapause.

    Thompson, Andrew W; Ortí, Guillermo

    2016-09-01

    Dormancy has evolved in all major metazoan lineages. It is critical for survival when environmental stresses are not conducive to growth, maturation, or reproduction. Embryonic diapause is a form of dormancy where development is reversibly delayed and metabolism is depressed. We report the diapause transcriptome of the annual killifish Nematolebias whitei, and compare gene expression between diapause embryos and free-living larvae to identify a candidate set of 945 differentially expressed "diapause" genes for this species. Similarity of transcriptional patterns among N. whitei and other diapausing animals is striking for a small set of genes associated with stress resistance, circadian rhythm, and metabolism, while other genes show discordant patterns. Although convergent evolution of diapause may require shared molecular mechanisms for fundamental processes, similar physiological phenotypes also may arise through modification of alternative pathways. Annual killifishes are a tractable model system for comparative transcriptomic studies on the evolution of diapause. PMID:27297470

  9. Genetic Variation in Candidate Genes Like the HMGA2 Gene in the Extremely Tall

    Hendriks, A. E. J.; Brown, M. R.; Boot, A. M.; Oostra, B. A.; Drop, S. L. S.; Parks, J. S.

    2011-01-01

    Background/Aims: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We the

  10. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

  11. Conserved co-expression for candidate disease gene prioritization

    Huynen Martijn A

    2008-04-01

    Full Text Available Abstract Background Genes that are co-expressed tend to be involved in the same biological process. However, co-expression is not a very reliable predictor of functional links between genes. The evolutionary conservation of co-expression between species can be used to predict protein function more reliably than co-expression in a single species. Here we examine whether co-expression across multiple species is also a better prioritizer of disease genes than is co-expression between human genes alone. Results We use co-expression data from yeast (S. cerevisiae, nematode worm (C. elegans, fruit fly (D. melanogaster, mouse and human and find that the use of evolutionary conservation can indeed improve the predictive value of co-expression. The effect that genes causing the same disease have higher co-expression than do other genes from their associated disease loci, is significantly enhanced when co-expression data are combined across evolutionarily distant species. We also find that performance can vary significantly depending on the co-expression datasets used, and just using more data does not necessarily lead to better prioritization. Instead, we find that dataset quality is more important than quantity, and using a consistent microarray platform per species leads to better performance than using more inclusive datasets pooled from various platforms. Conclusion We find that evolutionarily conserved gene co-expression prioritizes disease candidate genes better than human gene co-expression alone, and provide the integrated data as a new resource for disease gene prioritization tools.

  12. DRD4 and DAT1 in ADHD: Functional neurobiology to pharmacogenetics

    Darko Turic

    2010-05-01

    Full Text Available Darko Turic1, James Swanson2, Edmund Sonuga-Barke1,31Institute for Disorders of Impulse and Attention, School of Psychology, University of Southampton, UK; 2Child Development Center, University of California, Irvine, California, US; 3Department of Experimental, Clinical and Health Psychology, Ghent University, BelgiumAbstract: Attention deficit/hyperactivity disorder (ADHD is a common and potentially very impairing neuropsychiatric disorder of childhood. Statistical genetic studies of twins have shown ADHD to be highly heritable, with the combination of genes and gene by environment interactions accounting for around 80% of phenotypic variance. The initial molecular genetic studies where candidates were selected because of the efficacy of dopaminergic compounds in the treatment of ADHD were remarkably successful and provided strong evidence for the role of DRD4 and DAT1 variants in the pathogenesis of ADHD. However, the recent application of noncandidate gene strategies (eg, genome-wide association scans has failed to identify additional genes with substantial genetic main effects, and the effects for DRD4 and DAT1 have not been replicated. This is the usual pattern observed for most other physical and mental disorders evaluated with current state-of-the-art methods. In this paper we discuss future strategies for genetic studies in ADHD, highlighting both the pitfalls and possible solutions relating to candidate gene studies, genome-wide studies, defining the phenotype, and statistical approaches.Keywords: dopamine, ADHD, pharmacogenetics, candidate gene

  13. A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy

    Bruhn, Sören; Fang, Yu; Barrenäs, Fredrik;

    2014-01-01

    The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identi...

  14. Association of Dopamine Transporter Gene Variants with Childhood ADHD Features in Bipolar Disorder

    Greenwood, Tiffany A.; Joo, Eun-Jeong; Shektman, Tatyana; Sadovnick, A. Dessa; Remick, Ronald A.; Keck, Paul E; McElroy, Susan L; Kelsoe, John R.

    2012-01-01

    Bipolar Disorder (BD) and Attention Deficit Hyperactivity Disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, ...

  15. The role of ASTN2 variants in childhood and adult ADHD, comorbid disorders and associated personality traits.

    Freitag, Christine M; Lempp, Thomas; Nguyen, T Trang; Jacob, Christian P; Weissflog, Lena; Romanos, Marcel; Renner, Tobias J; Walitza, Susanne; Warnke, Andreas; Rujescu, Dan; Lesch, Klaus-Peter; Reif, Andreas

    2016-08-01

    Previous linkage and genome wide association (GWA) studies in ADHD indicated astrotactin 2 (ASTN2) as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). ASTN2 plays a key role in glial-guided neuronal migration. To investigate whether common variants in ASTN2 contribute to ADHD disorder risk, we tested 63 SNPs spanning ASTN2 for association with ADHD and specific comorbid disorders in two samples: 171 families of children with ADHD and their parents (N = 592), and an adult sample comprising 604 adult ADHD cases and 974 controls. The C-allele of rs12376789 in ASTN2 nominally increased the risk for ADHD in the trio sample (p = 0.025). This was not observed in the adult case-control sample alone, but retained in the combined sample (nominal p = 0.030). Several other SNPs showed nominally significant association with comorbid disorders, especially anxiety disorder, in the childhood and adult ADHD samples. Some ASTN2 variants were nominally associated with personality traits in the adult ADHD sample and overlapped with risk alleles for comorbid disorders in childhood. None of the findings survived correction for multiple testing, thus, results do not support a major role of common variants in ASTN2 in the pathogenesis of ADHD, its comorbid disorders or ADHD associated personality traits. PMID:27138430

  16. Novel primary immunodeficiency candidate genes predicted by the human gene connectome

    Yuval eItan

    2015-04-01

    Full Text Available Germline genetic mutations underlie various primary immunodeficiency (PID diseases. Patients with rare PID diseases (like most non-PID patients and healthy individuals carry, on average, 20,000 rare and common coding variants detected by high throughput sequencing. It is thus a major challenge to select only a few candidate disease-causing variants for experimental testing. One of the tools commonly used in the pipeline for estimating a potential PID candidate gene is to test whether the specific gene is included in the list of genes that were already experimentally validated as PID-causing in previous studies. However, this approach is limited because it cannot detect the PID-causing mutation(s in the many PID patients carrying causal mutations of as yet unidentified PID-causing genes. In this study, we expanded in silico the list of potential PID-causing candidate genes from 229 to 3,110. We first identified the top 1% of human genes predicted by the human genes connectome to be biologically close to the 229 known PID genes. We then further narrowed down the list of genes by retaining only the most biologically relevant genes, with functionally enriched gene ontology biological categories similar to those for the known PID genes. We validated this prediction by showing that 17 of the 21 novel PID genes published since the last IUIS classification fall into this group of 3,110 genes (p<10-7. The resulting new extended list of 3,110 predicted PID genes should be useful for the discovery of novel PID genes in patients.

  17. Identifying disease candidate genes via large-scale gene network analysis.

    Kim, Haseong; Park, Taesung; Gelenbe, Erol

    2014-01-01

    Gene Regulatory Networks (GRN) provide systematic views of complex living systems, offering reliable and large-scale GRNs to identify disease candidate genes. A reverse engineering technique, Bayesian Model Averaging-based Networks (BMAnet), which ensembles all appropriate linear models to tackle uncertainty in model selection that integrates heterogeneous biological data sets is introduced. Using network evaluation metrics, we compare the networks that are thus identified. The metric 'Random walk with restart (Rwr)' is utilised to search for disease genes. In a simulation our method shows better performance than elastic-net and Gaussian graphical models, but topological quantities vary among the three methods. Using real-data, brain tumour gene expression samples consisting of non-tumour, grade III and grade IV are analysed to estimate networks with a total of 4422 genes. Based on these networks, 169 brain tumour-related candidate genes were identified and some were found to relate to 'wound', 'apoptosis', and 'cell death' processes. PMID:25796737

  18. Investigation of two candidate genes for Hailey-Hailey disease

    Peluso, A.M.; Ikeda, S.; Bonifas, J.M. [Univ. of California, San Francisco, CA (United States)] [and others

    1994-09-01

    Hailey-Hailey disease (familial benign chronic pemphigus) is an autosomal dominant skin disease characterized by impaired keratinocyte cohesion and consequent blister formation. Recently we have used linkage to map the gene for this disease to a region of chromosome 3q between D3S1589 and D3S1316. The maximum combined two point lod score in four families studied was 14.60 at {theta} = 0 at the D3S1290 microsatellite repeat. Several genes have been mapped to chromosome 3q21-24, including cellular retinol binding protein (RBP1) and rhodopsin (RHO). Using microsatellite repeat for RHO we have found a recombinant with the RHO gene and Hailey-Hailey disease in one patient. Because of the profound effects of retinoids on epidermal differentiation, RBP1 could be considered as a possible candidate gene. We have amplified genomic DNA from patients from 14 individual families with Hailey-Hailey disease and 10 different control samples for each of the 4 exons of RBP1. Thus far, SSCP analysis has failed to detect different banding patterns in patients versus controls. We are now attempting to extend this RBP1 analysis and are collecting new families to use linkage analysis to narrow this still rather large (approximately 14 cM) interval.

  19. Expression cloning of a candidate gene for Mucolipidosis type IV

    Gama Sosa, M.A.; De Gasperi, R.; Battistini, S. [New York Univ. School of Medicine, NY (United States)] [and others

    1994-09-01

    Mucolipidosis IV is an autosomal recessive lysosomal storage disease characterized by progressive psychomotor retardation and opthalmological abnormalities, namely corneal opacity and retinal degeneration. Biochemically, it is characterized by the lysosomal accumulation of diverse compounds such as gangliosides, phospholipids and acidic mucopolysaccharides. To date, the basic biochemical defect causing this storage disease is still unknown and the relevant gene has also not been identified. An expression cloning strategy was used to identify human kidney cDNA clones capable of reverting in transient gene expression assays the PAS+ phenotype typical of Mucolipidosis IV cells to the normal PAS- phenotype. By this method, a candidate cDNA clone (Mu cDNA) capable of clearing Mucolipidosis IV fibroblasts of their PAS+ positive storage material was isolated. Nucleotide sequence analysis indicated the presence of 2 open reading frames. In vitro translation of T7 transcribed Mu RNA showed protein products of 7,000 and 6,000 mw. Altered expression of the Mu gene may result in the onset of Mucolipidosis type IV.

  20. Length of Selection Around Candidate Genes for Artificial Selection During Domestication and Crop Improvement in Maize

    Genomic screens for artificial selection have been successful in identifying candidate genes for agronomic traits in maize (Zea mays L). However, the validity of the candidates identified requires that selection sweeps are very short, only containing the candidate gene with the nearest neighboring g...

  1. Candidate Genes Detected in Transcriptome Studies are Strongly Dependent on Genetic Background

    Sarup, Pernille Merete; Sørensen, Jesper Givskov; Kristensen, Torsten Nygård; Hoffmann, Ary Anthony; Loeschcke, Volker; Paige, Ken N; Sørensen, Peter

    2011-01-01

    Whole genome transcriptomic studies can point to potential candidate genes for organismal traits. However, the importance of potential candidates is rarely followed up through functional studies and/or by comparing results across independent studies. We have analysed the overlap of candidate gene...

  2. Computational selection and prioritization of candidate genes for Fetal Alcohol Syndrome

    Hide Winston

    2007-10-01

    Full Text Available Abstract Background Fetal alcohol syndrome (FAS is a serious global health problem and is observed at high frequencies in certain South African communities. Although in utero alcohol exposure is the primary trigger, there is evidence for genetic- and other susceptibility factors in FAS development. No genome-wide association or linkage studies have been performed for FAS, making computational selection and -prioritization of candidate disease genes an attractive approach. Results 10174 Candidate genes were initially selected from the whole genome using a previously described method, which selects candidate genes according to their expression in disease-affected tissues. Hereafter candidates were prioritized for experimental investigation by investigating criteria pertinent to FAS and binary filtering. 29 Criteria were assessed by mining various database sources to populate criteria-specific gene lists. Candidate genes were then prioritized for experimental investigation using a binary system that assessed the criteria gene lists against the candidate list, and candidate genes were scored accordingly. A group of 87 genes was prioritized as candidates and for future experimental validation. The validity of the binary prioritization method was assessed by investigating the protein-protein interactions, functional enrichment and common promoter element binding sites of the top-ranked genes. Conclusion This analysis highlighted a list of strong candidate genes from the TGF-β, MAPK and Hedgehog signalling pathways, which are all integral to fetal development and potential targets for alcohol's teratogenic effect. We conclude that this novel bioinformatics approach effectively prioritizes credible candidate genes for further experimental analysis.

  3. Genetics of intracerebral hemorrhage: Insights from candidate gene approaches

    Baoqiong Liu

    2012-01-01

    Full Text Available Intracerebral hemorrhage (ICH is a heterogeneous disease with genetic factors playing an important role. Association studies on a wide range of candidate pathways suggest a weak but significant effect for several alleles with ICH risk. Among the most widely investigated genes are those involved in the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme, coagulation pathway (e.g., Factor XIII, Factor VII, platelet-activating factor acetylhydrolase, Factor V Leiden, and beta1-tubulin, lipid metabolism (e.g., apolipoproteins (ApoE, Apo(a, ApoH, homocysteine metabolism (e.g., methylenetetrahydrofolate reductase, inflammation (e.g., interleukin-6 and tumor necrosis-alpha and other candidate pathways. To identify the robustness of the above associations with ICH, a search of Pubmed (1988 through December 2011 was performed, with searches limited to English-language studies conducted among adult human subjects. This article presents a review of the examined literature on the genetics of ICH.

  4. 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 ...

  5. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD.

    Franke, B.; Vasquez, A.A.; Johansson, S.; Hoogman, M.; Romanos, J.; Boreatti-Hummer, A.; Heine, M.; Jacob, C.P.; Lesch, K.P.; Casas, M.; Ribases, M.; Bosch, R.; Sanchez-Mora, C.; Gomez-Barros, N.; Fernandez-Castillo, N.; Bayes, M.; Halmoy, A.; Halleland, H.; Landaas, E.T.; Fasmer, O.B.; Knappskog, P.M.; Heister, J.G.A.M.; Kiemeney, L.A.L.M.; Kooij, J.J.; Boonstra, A.M.; Kan, C.C.; Asherson, P.; Faraone, S.V.; Buitelaar, J.K.; Haavik, J.; Cormand, B.; Ramos-Quiroga, J.A.; Reif, A.

    2010-01-01

    Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4-5% in children and 1-4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there

  6. Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population

    Paracchini, S; Ang, Q W; Stanley, F J; Monaco, A. P.; Pennell, C E; Whitehouse, A J O

    2011-01-01

    Several genes have been suggested as dyslexia candidates. Some of these candidate genes have been recently shown to be associated with literacy measures in sample cohorts derived from the general population. Here, we have conducted an association study in a novel sample derived from the Australian population (the Raine cohort) to further investigate the role of dyslexia candidate genes. We analysed markers, previously reported to be associated with dyslexia, located within the MRPL19/C2ORF3, ...

  7. A candidate gene investigation of methylphenidate response in adult attention-deficit/hyperactivity disorder patients: results from a naturalistic study.

    Hegvik, Tor-Arne; Jacobsen, Kaya Kvarme; Fredriksen, Mats; Zayats, Tetyana; Haavik, Jan

    2016-08-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common childhood onset neuropsychiatric disorder with a complex and heterogeneous symptomatology. Persistence of ADHD symptoms into adulthood is common. Methylphenidate (MPH) is a widely prescribed stimulant compound that may be effective against ADHD symptoms in children and adults. However, MPH does not exert satisfactory effect in all patients. Several genetic variants have been proposed to predict either treatment response or adverse effects of stimulants. We conducted a literature search to identify previously reported variants associated with MPH response and additional variants that were biologically plausible candidates for MPH response. The response to MPH was assessed by the treating clinicians in 564 adult ADHD patients and 20 genetic variants were successfully genotyped. Logistic regression was used to test for association between these polymorphisms and treatment response. Nominal associations (p nominal significance level (OR 0.560, 95 % CI 0.329-0.953, p = 0.033). However, this finding was not affirmed in the meta-analysis. No genetic variants revealed significant associations after correction for multiple testing (p < 0.00125). Our results suggest that none of the studied variants are strong predictors of MPH response in adult ADHD as judged by clinician ratings, potentially except for rs1800544. Consequently, pharmacogenetic testing in routine clinical care is not supported by our analyses. Further studies on the pharmacogenetics of adult ADHD are warranted. PMID:27091191

  8. fMRI Activation during Response Inhibition and Error Processing: The Role of the DAT1 Gene in Typically Developing Adolescents and Those Diagnosed with ADHD

    Braet, Wouter; Johnson, Katherine A.; Tobin, Claire T.; Acheson, Ruth; McDonnell, Caroline; Hawi, Ziarah; Barry, Edwina; Mulligan, Aisling; Gill, Michael; Bellgrove, Mark A.; Robertson, Ian H.; Garavan, Hugh

    2011-01-01

    The DAT1 gene codes for the dopamine transporter, which clears dopamine from the synaptic cleft, and a variant of this gene has previously been associated with compromised response inhibition in both healthy and clinical populations. This variant has also been associated with ADHD, a disorder that is characterised by disturbed dopamine function as…

  9. Candidate genes for drought tolerance and improved productivity in rice (Oryza sativa L.)

    M S Vinod; Naveen Sharma; K Manjunatha; Adnan Kanbar; N B Prakash; H E Shashidhar

    2006-03-01

    Candidate genes are sequenced genes of known biological action involved in the development or physiology of a trait. Twenty-one putative candidate genes were designed after an exhaustive search in the public databases along with an elaborate literature survey for candidate gene products and/or regulatory sequences associated with enhanced drought resistance. The downloaded sequences were then used to design primers considering the flanking sequences as well. Polymerase chain reaction (PCR) performed on 10 diverse cultivars that involved Japonica, Indica and local accessions, revealed 12 polymorphic candidate genes. Seven polymorphic candidate genes were then utilized to genotype 148 individuals of CT9993 × IR62266 doubled haploid (DH) mapping population. The segregation data were tested for deviation from the expected Mendelian ratio (1:1) using a Chi-square test (<1%). Based on this, four candidate genes were assessed to be significant and the remaining three, as non-significant. All the significant candidate genes were biased towards CT9993, the female parent in the DH mapping population. Single-marker analysis strongly associated ( < 1%) them to different traits under both well-watered and low-moisture stress conditions. Two candidate genes, EXP15 and EXP13, were found to be associated with root number and silicon content in the stem respectively, under both well-watered and low-moisture stress conditions.

  10. Differential Gene Expression Reveals Candidate Genes for Drought Stress Response in Abies alba (Pinaceae)

    David Behringer; Heike Zimmermann; Birgit Ziegenhagen; Sascha Liepelt

    2015-01-01

    Increasing drought periods as a result of global climate change pose a threat to many tree species by possibly outpacing their adaptive capabilities. Revealing the genetic basis of drought stress response is therefore implemental for future conservation strategies and risk assessment. Access to informative genomic regions is however challenging, especially for conifers, partially due to their large genomes, which puts constraints on the feasibility of whole genome scans. Candidate genes offer...

  11. ADHD latent class clusters: DSM-IV subtypes and comorbidity.

    Elia, Josephine; Arcos-Burgos, Mauricio; Bolton, Kelly L; Ambrosini, Paul J; Berrettini, Wade; Muenke, Maximilian

    2009-12-30

    ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6-18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. PMID:19900717

  12. Database of cattle candidate genes and genetic markers for milk production and mastitis

    Ogorevc, J; Kunej, T; Razpet, A; Dovc, P

    2009-01-01

    A cattle database of candidate genes and genetic markers for milk production and mastitis has been developed to provide an integrated research tool incorporating different types of information supporting a genomic approach to study lactation, udder development and health. The database contains 943 genes and genetic markers involved in mammary gland development and function, representing candidates for further functional studies. The candidate loci were drawn on a genetic map to reveal positio...

  13. Exclusion of the PAX2 gene as a candidate gene for Crouzon craniofacial dysostosis

    Preston, R.A.; Gorry, M.C. [Univ. of Pittsburgh, PA (United States); Warman, M. [Harvard Univ., Boston, MA (United States)] [and others

    1994-09-01

    Crouzon craniofacial dysostosis (CFD, MIM 123500) is an abnormality of craniofacial development characterized by premature craniosynostosis, maxillary hypoplasia, and shallow orbits. We have mapped the CFD gene locus using a candidate gene approach to a 7 centiMorgan region on chromosome 10q in three CFD families. A maximal multipoint LOD score of 12.33 was achieved for a locus 2 cM distal to the microsatellite marker D10S209. A comparison of several physical, cytogenetic, and linkage maps revealed that the cytogenetic bands, 10q25-q26, most likely contain this CFD locus. The PAX2 gene, which has been mapped near another marker which in turn has been mapped to 10q25, was analyzed as a candidate gene. PAX2 was chosen for analysis because mutations in other members of the PAX gene family have been identified with human craniofacial abnormalities (e.g. Waardenburg syndrome). A YAC contig, consisting of 5 overlapping groups and composed of 11 YACs that spans the entire 7 cM region, was assembled for PAX2 analyses. None of these YACs supported PAX2-specific amplification using primer sets for both the second and third PAX2 exons. Control amplifications for YAC vector sequences produced robust amplifications in all cases. In addition, SSCP analyses of amplification products generated from the second and third PAX2 exons and the 3{prime} untranslated region of the PAX2 gene from both affected and unaffected family members in two of the kindreds failed to reveal any polymorphisms. Although it remains theoretically possible, due to artifacts in the YAC contigs, it is unlikely that PAX2 is the CFD gene.

  14. Fine mapping and candidate gene analysis of purple pericarp gene Pb in rice (Oryza sativa L.)

    2007-01-01

    Purple rice is a type of rice with anthocyanins deposited in its grain pericarp. The rice Pb gene controlling purple pericarp character is known to be on chromosome 4, and the purple color is dominant over white color. In this study, we fine mapped the Pb gene using two F2 segregating populations, i.e. Pei'ai 64S (white) × Yunanheixiannuo (purple) and Pei'ai 64S × Chuanheinuo (purple). In the first-pass mapping, the Pb gene was located in the region downstream the SSR marker RM3820. In the fine mapping, the candidate region was saturated with InDel and CAPS markers developed specifically for this study. Eventually, the Pb gene was mapped within the 25-kb region delimited by the upstream marker RID3 and the downstream marker RID4. The delimited region contained two annotated genes, Ra and bhlh16 (TIGR Rice Genome, R.5). The former is a homologue of the Myc transcription factor Lc controlling anthocyanin biosynthesis in maize, and the latter is a homologue of the TT8 gene, which is also an Myc transcription factor gene controlling the pericarp pigmentation in Arabidopsis thaliana. Sequence analysis showed that the exon 7 of the Ra gene of Yunanheixiannuo and Chuanheinuo had a 2-bp (GT) deletion compared with those of the white rice varieties Pei'ai 64S, 9311 and Nipponbare. A CAPS marker, CAPSRa, was developed according to the GT deletion for analysis of the two F2 segregating populations and 106 rice lines. The results showed that all F2 plants with white pericarp, and all non-purple rice lines (63 white and 22 red) contained no GT deletion, but all 20 purple rice lines contained the GT deletion. These results suggested that the Ra gene may be the Pb gene and the purple pericarp characteristic of rice is caused by the GT deletion within exon 7 of the Ra gene.

  15. Identification of Candidate Genes related to Bovine Marbling using Protein-Protein Interaction Networks

    Lim, Dajeong; Kim, Nam-Kuk; Park, Hye-Sun; Lee, Seung-Hwan; Cho, Yong-Min; Oh, Sung Jong; Kim, Tae-Hun; Kim, Heebal

    2011-01-01

    Complex traits are determined by the combined effects of many loci and are affected by gene networks or biological pathways. Systems biology approaches have an important role in the identification of candidate genes related to complex diseases or traits at the system level. The present study systemically analyzed genes associated with bovine marbling score and identified their relationships. The candidate nodes were obtained using MedScan text-mining tools and linked by protein-protein intera...

  16. Identification of candidate methylation-responsive genes in ovarian cancer

    Dickerson Erin B

    2007-01-01

    Full Text Available Abstract Background Aberrant methylation of gene promoter regions has been linked to changes in gene expression in cancer development and progression. Genes associated with CpG islands (CGIs are especially prone to methylation, but not all CGI-associated genes display changes in methylation patterns in cancers. Results In order to identify genes subject to regulation by methylation, we conducted gene expression profile analyses of an ovarian cancer cell line (OVCAR-3 before and after treatment with the demethylating agent 5-aza-deoxycytidine (5-aza-dC. An overlapping subset of these genes was found to display significant differences in gene expression between normal ovarian surface epithelial cells and malignant cells isolated from ovarian carcinomas. While 40% of all human genes are associated with CGIs, > 94% of the overlapping subset of genes is associated with CGIs. The predicted change in methylation status of genes randomly selected from the overlapping subset was experimentally verified. Conclusion We conclude that correlating genes that are upregulated in response to 5-aza-dC treatment of cancer cell lines with genes that are down-regulated in cancer cells may be a useful method to identify genes experiencing epigenetic-mediated changes in expression over cancer development.

  17. DRD4 Rare Variants in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence from a Birth Cohort Study

    Tovo-Rodrigues, Luciana; Rohde, Luis A.; Ana M. B. Menezes; Polanczyk, Guilherme V; Kieling, Christian; Julia P Genro; Anselmi, Luciana; Mara H. Hutz

    2013-01-01

    The dopamine receptor D4 (DRD4) is one of the most studied candidate genes for Attention-Deficit/Hyperactivity Disorder (ADHD). An excess of rare variants and non-synonymous mutations in the VNTR region of 7R allele in ADHD subjects was observed in previous studies with clinical samples. We hypothesize that genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. The subjects included in the present study are members of the 1993 Pelotas Birth Cohort Study (N=5,...

  18. Identification of candidate B-lymphoma genes by cross-species gene expression profiling.

    Van S Tompkins

    Full Text Available Comparative genome-wide expression profiling of malignant tumor counterparts across the human-mouse species barrier has a successful track record as a gene discovery tool in liver, breast, lung, prostate and other cancers, but has been largely neglected in studies on neoplasms of mature B-lymphocytes such as diffuse large B cell lymphoma (DLBCL and Burkitt lymphoma (BL. We used global gene expression profiles of DLBCL-like tumors that arose spontaneously in Myc-transgenic C57BL/6 mice as a phylogenetically conserved filter for analyzing the human DLBCL transcriptome. The human and mouse lymphomas were found to have 60 concordantly deregulated genes in common, including 8 genes that Cox hazard regression analysis associated with overall survival in a published landmark dataset of DLBCL. Genetic network analysis of the 60 genes followed by biological validation studies indicate FOXM1 as a candidate DLBCL and BL gene, supporting a number of studies contending that FOXM1 is a therapeutic target in mature B cell tumors. Our findings demonstrate the value of the "mouse filter" for genomic studies of human B-lineage neoplasms for which a vast knowledge base already exists.

  19. Transcriptome network analysis reveals candidate genes for renal cell carcinoma

    Wei Zhai; Yun-Fei Xu; Min Liu; Jun-Hua Zheng

    2012-01-01

    Context: Renal cell carcinoma (RCC) is a kidney cancer that originates in renal parenchyma and it is the most common type of kidney cancer with approximately 80% lethal cases. Aims: To interpret the mechanism, explore the regulation of TF-target genes and TF-pathway, and identify the potential key genes of renal cell carcinoma. Settings and Design: After constructing a regulation network from differently expressed genes and transcription factors, pathway regulation network and gene onto...

  20. Comprehensive phenotype/genotype analyses of the norepinephrine transporter gene (SLC6A2 in ADHD: relation to maternal smoking during pregnancy.

    Geeta A Thakur

    Full Text Available OBJECTIVE: Despite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD. METHODS: Children (6-12 years old diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT, including categorical and quantitative trait analyses, were conducted in 377 nuclear families. RESULTS: A highly significant association was observed with rs36021 (and linked SNPs in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002, behavioral assessments by parents (CBCL, P=0.00008, as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006 and parents (P=0.006. In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001, parents (Z=2.62, P=0.009, as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003. CONCLUSIONS: By using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment

  1. Molecular Evolution of Candidate Genes for Crop-Related Traits in Sunflower (Helianthus annuus L.)

    Mandel, Jennifer R.; McAssey, Edward V.; Nambeesan, Savithri; García-Navarro, Elena; Burke, John M.

    2014-01-01

    Evolutionary analyses aimed at detecting the molecular signature of selection during crop domestication and/or improvement can be used to identify genes or genomic regions of likely agronomic importance. Here, we describe the DNA sequence-based characterization of a pool of candidate genes for crop-related traits in sunflower. These genes, which were identified based on homology to genes of known effect in other study systems, were initially sequenced from a panel of improved lines. All genes...

  2. Genetics of human longevity with emphasis on the relevance of HSP70 as candidate genes

    Singh, Ripudaman; Kølvrå, Steen; Rattan, Suresh I S

    2007-01-01

    mechanisms. One such pathway includes the battery of stress response genes, especially the heat shock protein HSP70 genes. Three such genes, HSPA1A, HSPA1B and HSPA1L, are present within the MHC-III region on the short arm of chromosome 6. We and others have found alleles, genotypes and haplotypes which have...... heat shock. Stress response genes, particularly HSP70, are now the major candidates in the gene-longevity association studies....

  3. Expression of the dyslexia candidate gene kiaa0319-like in insect cells

    Holster, S.; Oers, van M.M.; Roode, E.C.; Tsang, O.W.H.; Yeung, V.S.Y.; Vlak, J.M.; Waye, M.M.Y.

    2013-01-01

    The human kiaa0319-like gene is one of the candidate genes for developmental dyslexia, but the exact function of the encoded KIAA0319L (KL) protein is not known. To allow functional analysis a purified, biologically active KL protein is required. The kiaa0319-like gene was expressed in insect cells

  4. Epidermal growth factor gene is a newly identified candidate gene for gout.

    Han, Lin; Cao, Chunwei; Jia, Zhaotong; Liu, Shiguo; Liu, Zhen; Xin, Ruosai; Wang, Can; Li, Xinde; Ren, Wei; Wang, Xuefeng; Li, Changgui

    2016-01-01

    Chromosome 4q25 has been identified as a genomic region associated with gout. However, the associations of gout with the genes in this region have not yet been confirmed. Here, we performed two-stage analysis to determine whether variations in candidate genes in the 4q25 region are associated with gout in a male Chinese Han population. We first evaluated 96 tag single nucleotide polymorphisms (SNPs) in eight inflammatory/immune pathway- or glucose/lipid metabolism-related genes in the 4q25 region in 480 male gout patients and 480 controls. The SNP rs12504538, located in the elongation of very-long-chain-fatty-acid-like family member 6 gene (Elovl6), was found to be associated with gout susceptibility (Padjusted = 0.00595). In the second stage of analysis, we performed fine mapping analysis of 93 tag SNPs in Elovl6 and in the epidermal growth factor gene (EGF) and its flanking regions in 1017 male patients gout and 1897 healthy male controls. We observed a significant association between the T allele of EGF rs2298999 and gout (odds ratio = 0.77, 95% confidence interval = 0.67-0.88, Padjusted = 6.42 × 10(-3)). These results provide the first evidence for an association between the EGF rs2298999 C/T polymorphism and gout. Our findings should be validated in additional populations. PMID:27506295

  5. Candidate gene analysis of organ pigmentation loci in the Solanaceae

    Thorup, T. A.; Tanyolac, B.; Livingstone, K D; Popovsky, S.; Paran, I.; Jahn, Molly

    2000-01-01

    Ten structural genes from the Capsicum (pepper) carotenoid biosynthetic pathway have been localized on a (Capsicum annuum × Capsicum chinense)F2 genetic map anchored in Lycopersicon (tomato). The positions of these genes were compared with positions of the same genes in tomato when known, and with loci from pepper, potato, and tomato that affect carotenoid levels in different tissues. C2, one of three phenotypically defined loci determining pepper fruit color, ...

  6. Identification of microdeletions in candidate genes for cleft lip and/or palate

    Shi, Min; Mostowska, Adrianna; Jugessur, Astanand;

    2009-01-01

    contribute to a particular disease. METHODS: We performed a candidate gene analysis involving 1,221 SNPs in 333 candidate genes for orofacial clefting, using 2,823 samples from 725 two- and three-generation families with a proband having cleft lip with or without cleft palate. We used SNP genotyping, DNA......, TBX1, and TFAP2A are likely to be etiologic. CONCLUSIONS: These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an...... efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general....

  7. Using the candidate gene approach for detecting genes underlying seed oil concentration and yield in soybean.

    Eskandari, Mehrzad; Cober, Elroy R; Rajcan, Istvan

    2013-07-01

    Increasing the oil concentration in soybean seeds has been given more attention in recent years because of demand for both edible oil and biodiesel production. Oil concentration in soybean is a complex quantitative trait regulated by many genes as well as environmental conditions. To identify genes governing seed oil concentration in soybean, 16 putative candidate genes of three important gene families (GPAT: acyl-CoA:sn-glycerol-3-phosphate acyltransferase, DGAT: acyl-CoA:diacylglycerol acyltransferase, and PDAT: phospholipid:diacylglycerol acyltransferase) involved in triacylglycerol (TAG) biosynthesis pathways were selected and their sequences retrieved from the soybean database ( http://www.phytozome.net/soybean ). Three sequence mutations were discovered in either coding or noncoding regions of three DGAT soybean isoforms when comparing the parents of a 203 recombinant inbreed line (RIL) population; OAC Wallace and OAC Glencoe. The RIL population was used to study the effects of these mutations on seed oil concentration and other important agronomic and seed composition traits, including seed yield and protein concentration across three field locations in Ontario, Canada, in 2009 and 2010. An insertion/deletion (indel) mutation in the GmDGAT2B gene in OAC Wallace was significantly associated with reduced seed oil concentration across three environments and reduced seed yield at Woodstock in 2010. A mutation in the 3' untranslated (3'UTR) region of GmDGAT2C was associated with seed yield at Woodstock in 2009. A mutation in the intronic region of GmDGAR1B was associated with seed yield and protein concentration at Ottawa in 2010. The genes identified in this study had minor effects on either seed yield or oil concentration, which was in agreement with the quantitative nature of the traits. However, the novel gene-specific markers designed in the present study can be used in soybean breeding for marker-assisted selection aimed at increasing seed yield and oil

  8. Predicting sensation seeking from dopamine genes: A candidate system approach

    Derringer, Jaime; Robert F Krueger; Dick, Danielle M; Saccone, Scott; Grucza, Richard A.; Agrawal, Arpana; Lin, Peng; Almasy, Laura; Edenberg, Howard J.; Foroud, Tatiana; Nurnberger, John I.; Hesselbrock, Victor M.; Kramer, John R.; Kuperman, Samuel; Porjesz, Bernice

    2010-01-01

    Sensation seeking is a heritable personality trait that has been reliably linked to behavior disorders. The dopamine system has been hypothesized to contribute to individual differences in sensation seeking, and both experimental and observational studies in humans and non-human animals provide evidence for this relationship. We present here a candidate-system approach to genetic association analysis of sensation seeking, in which single nucleotide polymorphisms (SNPs) from a number of dopami...

  9. Functional epigenomics approach to identify methylated candidate tumour suppressor genes in renal cell carcinoma

    Morris, M.

    2008-01-01

    Promoter region hypermethylation and transcriptional silencing is a frequent cause of tumour suppressor gene (TSG) inactivation in many human cancers. Previously, to identify candidate epigenetically inactivated TSGs in renal cell carcinoma (RCC), we monitored changes in gene expression in four RCC cell lines after treatment with the demethylating agent 5-azacytidine. This enabled us to identify HAI-2/SPINT2 as a novel epigenetically inactivated candidate RCC TSG. To identify further candidat...

  10. Quantitative DNA methylation analysis of candidate genes in cervical cancer.

    Erin M Siegel

    Full Text Available Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2. A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003. Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated.

  11. Quantitative DNA methylation analysis of candidate genes in cervical cancer.

    Siegel, Erin M; Riggs, Bridget M; Delmas, Amber L; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and 22 women with normal cytology specimens. Bisulfite-modified genomic DNA was amplified and quantitative pyrosequencing completed for 10 genes (APC, CCNA, CDH1, CDH13, WIF1, TIMP3, DAPK1, RARB, FHIT, and SLIT2). A Methylation Index was calculated as the mean percent methylation across all CpG sites analyzed per gene (~4-9 CpG site) per sequence. A binary cut-point was defined at >15% methylation. Sensitivity, specificity and area under ROC curve (AUC) of methylation in individual genes or a panel was examined. The median methylation index was significantly higher in cases compared to controls in 8 genes, whereas there was no difference in median methylation for 2 genes. Compared to HPV and age, the combination of DNA methylation level of DAPK1, SLIT2, WIF1 and RARB with HPV and age significantly improved the AUC from 0.79 to 0.99 (95% CI: 0.97-1.00, p-value = 0.003). Pyrosequencing analysis confirmed that several genes are common targets for aberrant methylation in cervical cancer and DNA methylation level of four genes appears to increase specificity to identify cancer compared to HPV detection alone. Alterations in DNA methylation of specific genes in cervical cancers, such as DAPK1, RARB, WIF1, and SLIT2, may also occur early in cervical carcinogenesis and should be evaluated. PMID:25826459

  12. Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes

    Russell, Meaghan K; Longoni, Mauro; Wells, Julie;

    2012-01-01

    expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental...... undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies....... perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes...

  13. Quantitative DNA Methylation Analysis of Candidate Genes in Cervical Cancer

    Erin M Siegel; Riggs, Bridget M; Delmas, Amber L.; Koch, Abby; Hakam, Ardeshir; Brown, Kevin D.

    2015-01-01

    Aberrant DNA methylation has been observed in cervical cancer; however, most studies have used non-quantitative approaches to measure DNA methylation. The objective of this study was to quantify methylation within a select panel of genes previously identified as targets for epigenetic silencing in cervical cancer and to identify genes with elevated methylation that can distinguish cancer from normal cervical tissues. We identified 49 women with invasive squamous cell cancer of the cervix and ...

  14. Candidate gene linkage analysis indicates genetic heterogeneity in Marfan syndrome

    L.V.S. Teixeira

    2011-08-01

    Full Text Available Marfan syndrome (MFS is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34 of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

  15. Aberrant methylation of candidate tumor suppressor genes in neuroblastoma.

    Hoebeeck, Jasmien; Michels, Evi; Pattyn, Filip; Combaret, Valérie; Vermeulen, Joëlle; Yigit, Nurten; Hoyoux, Claire; Laureys, Geneviève; De Paepe, Anne; Speleman, Frank; Vandesompele, Jo

    2009-01-18

    CpG island hypermethylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation. In this study, we performed methylation-specific PCR (MSP) to investigate the methylation status of 10 selected tumor suppressor genes in neuroblastoma. Seven of the investigated genes (CD44, RASSF1A, CASP8, PTEN, ZMYND10, CDH1, PRDM2) showed high frequencies (> or =30%) of methylation in 33 neuroblastoma cell lines. In 42 primary neuroblastoma tumors, the frequencies of methylation were 69%, CD44; 71%, RASSF1A; 56%, CASP8; 25%, PTEN; 15%, ZMYND10; 8%, CDH1; and 0%, PRDM2. Furthermore, CASP8 and CDH1 hypermethylation was significantly associated with poor event-free survival. Meta-analysis of 115 neuroblastoma tumors demonstrated a significant correlation between CASP8 methylation and MYCN amplification. In addition, there was a correlation between ZMYND10 methylation and MYCN amplification. The MSP data, together with optimized mRNA re-expression experiments (in terms of concentration and time of treatment and use of proper reference genes) further strengthen the notion that epigenetic alterations could play a significant role in NB oncogenesis. This study thus warrants the need for a global profiling of gene promoter hypermethylation to identify genome-wide aberrantly methylated genes in order to further understand neuroblastoma pathogenesis and to identify prognostic methylation markers. PMID:18819746

  16. Transcriptome network analysis reveals potential candidate genes for squamous lung cancer.

    Bai, Jing; Hu, Sheng

    2012-01-01

    Squamous lung cancer is a common type of lung cancer; however, its mechanism of oncogenesis is still unknown. The aim of this study was to screen candidate genes of squamous lung cancer using a bioinformatics strategy and elucidate the mechanism of squamous lung cancer. Published microarray data of the GSE3268 series was obtained from Gene Expression Omnibus (GEO). Significance analysis of microarrays was performed using the software R, and differentially expressed genes by R analysis were harvested. The relationship between transcription factors and target genes in cancer were collected from the Transcriptional regulatory element database. A transcriptome network analysis method was used to construct gene regulation networks and select the candidate genes for squamous lung cancer. SPI1, FLI1, FOS, ETS2, EGR1 and PPARG were defined as candidate genes for squamous lung cancer by the transcriptome network analysis method. Among them, 5 genes had been reported to be involved in lung cancer, except SPI1 and FLI1. Effective recall on previous knowledge conferred strong confidence in these methods. It is demonstrated that transcriptome network analysis is useful in the identification of candidate genes in disease. PMID:21922129

  17. Candidates in Astroviruses, Seadornaviruses, Cytorhabdoviruses and Coronaviruses for +1 frame overlapping genes accessed by leaky scanning

    Atkins John F

    2010-01-01

    Full Text Available Abstract Background Overlapping genes are common in RNA viruses where they serve as a mechanism to optimize the coding potential of compact genomes. However, annotation of overlapping genes can be difficult using conventional gene-finding software. Recently we have been using a number of complementary approaches to systematically identify previously undetected overlapping genes in RNA virus genomes. In this article we gather together a number of promising candidate new overlapping genes that may be of interest to the community. Results Overlapping gene predictions are presented for the astroviruses, seadornaviruses, cytorhabdoviruses and coronaviruses (families Astroviridae, Reoviridae, Rhabdoviridae and Coronaviridae, respectively.

  18. Attention deficit hyperactivity disorder (ADHD): review for primary care clinicians

    Ougrin, Dennis; Chatterton, Sandie; Banarsee, Ricky

    2010-01-01

    Attention deficit hyperactivity disorder (ADHD) is characterised by impulsivity, hyperactivity and inattention. Up to 5% of primary school age children have ADHD. Both genes and environment play a role in the aetiology of ADHD. If left untreated, children with ADHD demonstrate a range of poor long-term psychosocial outcomes. The Strengths and Difficulties Questionnaire (SDQ) may be used to screen children for a range of psychiatric disorders, including ADHD.1

  19. LOD score exclusion analyses for candidate disease susceptibility genes using case-parents design

    DENG Hongwen; GAO Guimin

    2006-01-01

    The focus of almost all the association studies of candidate genes is to test for their importance. We recently developed a LOD score approach that can be used to test against the importance of candidate genes for complex diseases and quantitative traits in random samples. As a complementary method to regular association analyses, our LOD score approach is powerful but still affected by the population admixture, though it is more conservative. To control the confounding effect of population heterogeneity, we develop here a LOD score exclusion analysis using case-parents design, the basic design of the transmission disequilibrium test (TDT) approach that is immune to population admixture. In the analysis, specific genetic effects and inheritance models at candidate genes can be analyzed and if a LOD score is ≤ - 2.0, the locus can be excluded from having an effect larger than that specified. Simulations show that this approach has reasonable power to exclude a candidate gene having small genetic effects if it is not a disease susceptibility locus (DSL) with sample size often employed in TDT studies. Similar to association analyses with the TDT in nuclear families, our exclusion analyses are generally not affected by population admixture. The exclusion analyses may be implemented to rule out candidate genes with no or minor genetic effects as supplemental analyses for the TDT. The utility of the approach is illustrated with an application to test the importance of vitamin D receptor (VDR) gene underlying the differential risk to osteoporosis.

  20. Mapping of Candidate Genes Involved in Bud Dormancy and Flowering Time in Sweet Cherry (Prunus avium.

    Sophie Castède

    Full Text Available The timing of flowering in perennial plants is crucial for their survival in temperate climates and is regulated by the duration of bud dormancy. Bud dormancy release and bud break depend on the perception of cumulative chilling during endodormancy and heat during the bud development. The objectives of this work were to identify candidate genes involved in dormancy and flowering processes in sweet cherry, their mapping in two mapping progenies 'Regina' × 'Garnet' and 'Regina' × 'Lapins', and to select those candidate genes which co-localized with quantitative trait loci (QTLs associated with temperature requirements for bud dormancy release and flowering. Based on available data on flowering processes in various species, a list of 79 candidate genes was established. The peach and sweet cherry orthologs were identified and primers were designed to amplify sweet cherry candidate gene fragments. Based on the amplified sequences of the three parents of the mapping progenies, SNPs segregations in the progenies were identified. Thirty five candidate genes were genetically mapped in at least one of the two progenies and all were in silico mapped. Co-localization between candidate genes and QTLs associated with temperature requirements and flowering date were identified for the first time in sweet cherry. The allelic composition of the candidate genes located in the major QTL for heat requirements and flowering date located on linkage group 4 have a significant effect on these two traits indicating their potential use for breeding programs in sweet cherry to select new varieties adapted to putative future climatic conditions.

  1. Mapping of Candidate Genes Involved in Bud Dormancy and Flowering Time in Sweet Cherry (Prunus avium).

    Castède, Sophie; Campoy, José Antonio; Le Dantec, Loïck; Quero-García, José; Barreneche, Teresa; Wenden, Bénédicte; Dirlewanger, Elisabeth

    2015-01-01

    The timing of flowering in perennial plants is crucial for their survival in temperate climates and is regulated by the duration of bud dormancy. Bud dormancy release and bud break depend on the perception of cumulative chilling during endodormancy and heat during the bud development. The objectives of this work were to identify candidate genes involved in dormancy and flowering processes in sweet cherry, their mapping in two mapping progenies 'Regina' × 'Garnet' and 'Regina' × 'Lapins', and to select those candidate genes which co-localized with quantitative trait loci (QTLs) associated with temperature requirements for bud dormancy release and flowering. Based on available data on flowering processes in various species, a list of 79 candidate genes was established. The peach and sweet cherry orthologs were identified and primers were designed to amplify sweet cherry candidate gene fragments. Based on the amplified sequences of the three parents of the mapping progenies, SNPs segregations in the progenies were identified. Thirty five candidate genes were genetically mapped in at least one of the two progenies and all were in silico mapped. Co-localization between candidate genes and QTLs associated with temperature requirements and flowering date were identified for the first time in sweet cherry. The allelic composition of the candidate genes located in the major QTL for heat requirements and flowering date located on linkage group 4 have a significant effect on these two traits indicating their potential use for breeding programs in sweet cherry to select new varieties adapted to putative future climatic conditions. PMID:26587668

  2. Whole genome amplification of DNA for genotyping pharmacogenetics candidate genes.

    Santosh ePhilips

    2012-03-01

    Full Text Available Whole genome amplification (WGA technologies can be used to amplify genomic DNA when only small amounts of DNA are available. The Multiple Displacement Amplification Phi polymerase based amplification has been shown to accurately amplify DNA for a variety of genotyping assays; however, it has not been tested for genotyping many of the clinically relevant genes important for pharmacogenetic studies, such as the cytochrome P450 genes, that are typically difficult to genotype due to multiple pseudogenes, copy number variations, and high similarity to other related genes. We evaluated whole genome amplified samples for Taqman™ genotyping of SNPs in a variety of pharmacogenetic genes. In 24 DNA samples from the Coriell human diversity panel, the call rates and concordance between amplified (~200-fold amplification and unamplified samples was 100% for two SNPs in CYP2D6 and one in ESR1. In samples from a breast cancer clinical trial (Trial 1, we compared the genotyping results in samples before and after WGA for four SNPs in CYP2D6, one SNP in CYP2C19, one SNP in CYP19A1, two SNPs in ESR1, and two SNPs in ESR2. The concordance rates were all >97%. Finally, we compared the allele frequencies of 143 SNPs determined in Trial 1 (whole genome amplified DNA to the allele frequencies determined in unamplified DNA samples from a separate trial (Trial 2 that enrolled a similar population. The call rates and allele frequencies between the two trials were 98% and 99.7%, respectively. We conclude that the whole genome amplified DNA is suitable for Taqman™ genotyping for a wide variety of pharmacogenetically relevant SNPs.

  3. Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes

    Lieberman, Tami D; Michel, Jean-Baptiste; Aingaran, Mythili; Potter-Bynoe, Gail; Roux, Damien; Davis, Michael R.; Skurnik, David; Leiby, Nicholas; LiPuma, John J.; Goldberg, Joanna B.; McAdam, Alexander J.; Priebe, Gregory P.; Kishony, Roy

    2011-01-01

    Bacterial pathogens evolve during the infection of their human hosts 1-8 , but separating adaptive and neutral mutations remains challenging 9-11 . Here, we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple patients. We conducted a retrospective study of a Burkholderia dolosa outbreak among people with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals ...

  4. A putative greigite-type magnetosome gene cluster from the candidate phylum Latescibacteria.

    Lin, Wei; Pan, Yongxin

    2015-04-01

    The intracellular biomineralization of magnetite and/or greigite magnetosomes in magnetotactic bacteria (MTB) is strictly controlled by a group of conserved genes, termed magnetosome genes, which are organized as clusters (or islands) in MTB genomes. So far, all reported MTB are affiliated within the Proteobacteria phylum, the Nitrospirae phylum and the candidate division OP3. Here, we report the discovery of a putative magnetosome gene cluster structure from the draft genome of an uncultivated bacterium belonging to the candidate phylum Latescibacteria (formerly candidate division WS3) recently recovered by Rinke and colleagues, which contains 10 genes with homology to magnetosome mam genes of magnetotactic Proteobacteria and Nitrospirae. Moreover, these genes are phylogenetically closely related to greigite-type magnetosome genes that were only found from the Deltaproteobacteria MTB before, suggesting that the greigite genes may originate earlier than previously imagined. These findings indicate that some members of Latescibacteria may be capable of forming greigite magnetosomes, and thus may play previously unrecognized roles in environmental iron and sulfur cycles. The conserved genomic structure of magnetosome gene cluster in Latescibacteria phylum supports the hypothesis of horizontal transfer of these genes among distantly related bacterial groups in nature. PMID:25382584

  5. Identifying Novel Candidate Genes Related to Apoptosis from a Protein-Protein Interaction Network

    Baoman Wang

    2015-01-01

    Full Text Available Apoptosis is the process of programmed cell death (PCD that occurs in multicellular organisms. This process of normal cell death is required to maintain the balance of homeostasis. In addition, some diseases, such as obesity, cancer, and neurodegenerative diseases, can be cured through apoptosis, which produces few side effects. An effective comprehension of the mechanisms underlying apoptosis will be helpful to prevent and treat some diseases. The identification of genes related to apoptosis is essential to uncover its underlying mechanisms. In this study, a computational method was proposed to identify novel candidate genes related to apoptosis. First, protein-protein interaction information was used to construct a weighted graph. Second, a shortest path algorithm was applied to the graph to search for new candidate genes. Finally, the obtained genes were filtered by a permutation test. As a result, 26 genes were obtained, and we discuss their likelihood of being novel apoptosis-related genes by collecting evidence from published literature.

  6. The complete spectrum of yeast chromosome instability genes identifies candidate CIN cancer genes and functional roles for ASTRA complex components.

    Peter C Stirling

    2011-04-01

    Full Text Available Chromosome instability (CIN is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼ 2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2 complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease.

  7. Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

    Rivero, O; Selten, M M; Sich, S; Popp, S; Bacmeister, L; Amendola, E; Negwer, M; Schubert, D; Proft, F; Kiser, D; Schmitt, A G; Gross, C; Kolk, S M; Strekalova, T; van den Hove, D; Resink, T J; Nadif Kasri, N; Lesch, K P

    2015-01-01

    Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13−/− mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13−/− mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism. PMID:26460479

  8. Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

    Rivero, O; Selten, M M; Sich, S; Popp, S; Bacmeister, L; Amendola, E; Negwer, M; Schubert, D; Proft, F; Kiser, D; Schmitt, A G; Gross, C; Kolk, S M; Strekalova, T; van den Hove, D; Resink, T J; Nadif Kasri, N; Lesch, K P

    2015-01-01

    Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13(-/-) mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13(-/-) mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism. PMID:26460479

  9. Using microarrays to identify positional candidate genes for QTL: the case study of ACTH response in pigs

    Jouffe, Vincent; Rowe, Suzanne; Liaubet, Laurence;

    2009-01-01

    Background: Microarray studies can supplement QTL studies by suggesting potential candidate. Microarray studies can supplement QTL studies by suggesting potential candidate genes in the QTL regions, which by themselves are too large to provide a limited selection of candidate genes. Here we provi...

  10. Integrating genes and phenotype: a wheat-Arabidopsis-rice glycosyltransferase database for candidate gene analyses.

    Sado, Pierre-Etienne; Tessier, Dominique; Vasseur, Marc; Elmorjani, Khalil; Guillon, Fabienne; Saulnier, Luc

    2009-02-01

    Glycosyltransferases (GTs) constitute a very large multi-gene superfamily, containing several thousand members identified in sequenced organisms especially in plants. GTs are key enzymes involved in various biological processes such as cell wall formation, storage polysaccharides biosynthesis, and glycosylation of various metabolites. GTs have been identified in rice (Oryza sativa) and Arabidopsis thaliana, but their precise function has been demonstrated biochemically for only a few. In this work we have established a repertoire of virtually all the wheat (Triticum aestivum) GT sequences, using the large publicly available banks of expressed sequences. Based on sequence similarity with Arabidopsis and rice GTs compiled in the carbohydrate active enzyme database (CAZY), we have identified and classified these wheat sequences. The results were used to feed a searchable database available on the web ( http://wwwappli.nantes.inra.fr:8180/GTIDB ) that can be used for initiating an exhaustive candidate gene survey in wheat applied to a particular biological process. This is illustrated through the identification of GT families which are expressed during cell wall formation in wheat grain maturation. PMID:19005709

  11. Hardy–Weinberg equilibrium analysis of the 48 bp VNTR in the III exon of the DRD4 gene in a sample of parents of ADHD cases

    Trejo S

    2015-06-01

    Full Text Available Salvador Trejo, José J Toscano-Flores, Esmeralda Matute, María de Lourdes Ramírez-Dueñas Laboratorio de Neuropsicología y Neurolingüística, Instituto de Neurociencias CUCBA, Guadalajara, Jalisco, Mexico Abstract: The aim of this study was to obtain the genotype and gene frequency from parents of children with attention-deficit/hyperactivity disorder (ADHD and then assess the Hardy–Weinberg equilibrium of genotype frequency of the variable number tandem repeat (VNTR III exon of the dopamine receptor D4 (DRD4 gene. The genotypes of the III exon of 48 bp VNTR repeats of the DRD4 gene were determined by polymerase chain reaction in a sample of 30 parents of ADHD cases. In the 60 chromosomes analyzed, the following frequencies of DRD4 gene polymorphisms were observed: six chromosomes (c with two repeat alleles (r (10%; 1c with 3r (1.5%; 36c with 4r (60%; 1c with 5r (1.5%; and 16c with 7r (27%. The genotypic distribution of the 30 parents was two parents (p with 2r/2r (6.67%; 1p with 2r/4r (3.33%; 1p with 2r/5r (3.33%; 1p with 3r/4r (3.33%; 15p with 4r/4r (50%; 4p with 4r/7r (13.33; and 6p with 7r/7r (20%. A Hardy–Weinberg disequilibrium (χ2=13.03, P<0.01 was found due to an over-representation of the 7r/7r genotype. These results suggest that the 7r polymorphism of the DRD4 gene is associated with the ADHD condition in a Mexican population. Keywords: ADHD, parents, DRD4, HWE

  12. Cholesterol tethered bioresponsive polycation as a candidate for gene delivery

    Zhu Ying [Second Affiliated Hospital, Medical College, Zhejiang University, Hangzhou 310009 (China); Wang Youxiang, E-mail: yx_wang@zju.edu.cn [Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027 (China); Key Laboratory of Macromolecular Synthesis and Functionalization, Ministry of Education, Zhejiang University, Hangzhou 310027 (China); Hu Qiaoling; Shen Jiacong [Department of Polymer Science and Engineering, Zhejiang University, Hangzhou 310027 (China); Key Laboratory of Macromolecular Synthesis and Functionalization, Ministry of Education, Zhejiang University, Hangzhou 310027 (China)

    2009-04-30

    The efficient unpacking of viral protein shell gave the inspiration for the synthesized vectors. In this research, novel cholesterol tethered bioresponsive polyethylenimine (PEI) was specially designed via disulfide-containing cross-linker. The cholesterol lipid had proved to increase the permeability of gene vector through cell membrane. The acid-base titration indicated that the synthesized polycation possessed efficient proton sponge effect, which was suggested to increase endosomal release of pDNA complexes into the cytoplasm. The cholesterol tethered polycation could effectively induce DNA condensation and form spherical particles with diameter about 200 nm at N/P ratio of 10. At glutathione concentration of 3 mM, the polyplexes were unpacked due to the bioresponsive cleavage of the disulfide bonds. The in-vitro experiment indicated that the polyplexes showed efficient transfection efficiency to HEK293T cells. All the results indicated that the bioresponsive polycation could be served as an effective trigger to control the release of DNA at the intracellular environment. The novel bioresponsive polycation might have great potential in non-viral gene delivery research and application.

  13. Cholesterol tethered bioresponsive polycation as a candidate for gene delivery

    The efficient unpacking of viral protein shell gave the inspiration for the synthesized vectors. In this research, novel cholesterol tethered bioresponsive polyethylenimine (PEI) was specially designed via disulfide-containing cross-linker. The cholesterol lipid had proved to increase the permeability of gene vector through cell membrane. The acid-base titration indicated that the synthesized polycation possessed efficient proton sponge effect, which was suggested to increase endosomal release of pDNA complexes into the cytoplasm. The cholesterol tethered polycation could effectively induce DNA condensation and form spherical particles with diameter about 200 nm at N/P ratio of 10. At glutathione concentration of 3 mM, the polyplexes were unpacked due to the bioresponsive cleavage of the disulfide bonds. The in-vitro experiment indicated that the polyplexes showed efficient transfection efficiency to HEK293T cells. All the results indicated that the bioresponsive polycation could be served as an effective trigger to control the release of DNA at the intracellular environment. The novel bioresponsive polycation might have great potential in non-viral gene delivery research and application.

  14. Identification of Candidate Genes related to Bovine Marbling using Protein-Protein Interaction Networks

    Dajeong Lim, Nam-Kuk Kim, Hye-Sun Park, Seung-Hwan Lee, Yong-Min Cho, Sung Jong Oh, Tae-Hun Kim, Heebal Kim

    2011-01-01

    Full Text Available Complex traits are determined by the combined effects of many loci and are affected by gene networks or biological pathways. Systems biology approaches have an important role in the identification of candidate genes related to complex diseases or traits at the system level. The present study systemically analyzed genes associated with bovine marbling score and identified their relationships. The candidate nodes were obtained using MedScan text-mining tools and linked by protein-protein interaction (PPI from the Human Protein Reference Database (HPRD. To determine key node of marbling, the degree and betweenness centrality (BC were used. The hub nodes and biological pathways of our network are consistent with the previous reports about marbling traits, and also suggest unknown candidate genes associated with intramuscular fat. Five nodes were identified as hub genes, which was consistent with the network analysis using quantitative reverse-transcription PCR (qRT-PCR. Key nodes of the PPI network have positive roles (PPARγ, C/EBPα, and RUNX1T1 and negative roles (RXRA, CAMK2A in the development of intramuscular fat by several adipogenesis-related pathways. This study provides genetic information for identifying candidate genes for the marbling trait in bovine.

  15. A transcription map of the 6p22.3 reading disability locus identifying candidate genes

    Gruen Jeffrey R

    2003-06-01

    Full Text Available Abstract Background Reading disability (RD is a common syndrome with a large genetic component. Chromosome 6 has been identified in several linkage studies as playing a significant role. A more recent study identified a peak of transmission disequilibrium to marker JA04 (G72384 on chromosome 6p22.3, suggesting that a gene is located near this marker. Results In silico cloning was used to identify possible candidate genes located near the JA04 marker. The 2 million base pairs of sequence surrounding JA04 was downloaded and searched against the dbEST database to identify ESTs. In total, 623 ESTs from 80 different tissues were identified and assembled into 153 putative coding regions from 19 genes and 2 pseudogenes encoded near JA04. The identified genes were tested for their tissue specific expression by RT-PCR. Conclusions In total, five possible candidate genes for RD and other diseases mapping to this region were identified.

  16. Mapping a candidate gene (MdMYB10 for red flesh and foliage colour in apple

    Allan Andrew C

    2007-07-01

    Full Text Available Abstract Background Integrating plant genomics and classical breeding is a challenge for both plant breeders and molecular biologists. Marker-assisted selection (MAS is a tool that can be used to accelerate the development of novel apple varieties such as cultivars that have fruit with anthocyanin through to the core. In addition, determining the inheritance of novel alleles, such as the one responsible for red flesh, adds to our understanding of allelic variation. Our goal was to map candidate anthocyanin biosynthetic and regulatory genes in a population segregating for the red flesh phenotypes. Results We have identified the Rni locus, a major genetic determinant of the red foliage and red colour in the core of apple fruit. In a population segregating for the red flesh and foliage phenotype we have determined the inheritance of the Rni locus and DNA polymorphisms of candidate anthocyanin biosynthetic and regulatory genes. Simple Sequence Repeats (SSRs and Single Nucleotide Polymorphisms (SNPs in the candidate genes were also located on an apple genetic map. We have shown that the MdMYB10 gene co-segregates with the Rni locus and is on Linkage Group (LG 09 of the apple genome. Conclusion We have performed candidate gene mapping in a fruit tree crop and have provided genetic evidence that red colouration in the fruit core as well as red foliage are both controlled by a single locus named Rni. We have shown that the transcription factor MdMYB10 may be the gene underlying Rni as there were no recombinants between the marker for this gene and the red phenotype in a population of 516 individuals. Associating markers derived from candidate genes with a desirable phenotypic trait has demonstrated the application of genomic tools in a breeding programme of a horticultural crop species.

  17. Social cognitive role of schizophrenia candidate gene GABRB2.

    Shui Ying Tsang

    Full Text Available The occurrence of positive selection in schizophrenia-associated GABRB2 suggests a broader impact of the gene product on population fitness. The present study considered the possibility of cognition-related GABRB2 involvement by examining the association of GABRB2 with psychosis and altruism, respectively representing psychiatric and psychological facets of social cognition. Four single nucleotide polymorphisms (SNPs were genotyped for quantitative trait analyses and population-based association studies. Psychosis was measured by either the Positive and Negative Syndrome Scale (PANSS or antipsychotics dosage, and altruism was based on a self-report altruism scale. The minor alleles of SNPs rs6556547, rs1816071 and rs187269 in GABRB2 were correlated with high PANSS score for positive symptoms in a Han Chinese schizophrenic cohort, whereas those of rs1816071 and rs1816072 were associated with high antipsychotics dosage in a US Caucasian schizophrenic cohort. Moreover, strongly significant GABRB2-disease associations were found among schizophrenics with severe psychosis based on high PANSS positive score, but no significant association was observed for schizophrenics with only mild psychosis. Interestingly, in addition to association with psychosis in schizophrenics, rs187269 was also associated with altruism in healthy Han Chinese. Furthermore, parallel to correlation with severe psychosis, its minor allele was correlated with high altruism scores. These findings revealed that GABRB2 is associated with psychosis, the core symptom and an endophenotype of schizophrenia. Importantly, the association was found across the breadth of the psychiatric (psychosis to psychological (altruism spectrum of social cognition suggesting GABRB2 involvement in human cognition.

  18. Third chromosome candidate genes for conspecific sperm precedence between D. simulans and D. mauritiana

    Brouwers Barb

    2010-04-01

    Full Text Available Abstract Background Male - female incompatibilities can be critical in keeping species as separate and discrete units. Premating incompatibilities and postzygotic hybrid sterility/inviability have been widely studied as isolating barriers between species. In recent years, a number of studies have brought attention to postmating prezygotic barriers arising from male - male competition and male - female interactions. Yet little is known about the genetic basis of postmating prezygotic isolation barriers between species. Results Using D. simulans lines with mapped introgressions of D. mauritiana into their third chromosome, we find at least two D. mauritiana introgressions causing male breakdown in competitive paternity success. Eighty one genes within the mapped introgressed regions were identified as broad-sense candidates on the basis of male reproductive tract expression and male-related function. The list of candidates was narrowed down to five genes based on differences in male reproductive tract expression between D. simulans and D. mauritiana. Another ten genes were confirmed as candidates using evidence of adaptive gene coding sequence diversification in the D. simulans and/or D. mauritiana lineage. Our results show a complex genetic basis for conspecific sperm precedence, with evidence of gene interactions between at least two third chromosome loci. Pleiotropy is also evident from correlation between conspecific sperm precedence and female induced fecundity and the identification of candidate genes that might exert an effect through genetic conflict and immunity. Conclusions We identified at least two loci responsible for conspecific sperm precedence. A third of candidate genes within these two loci are located in the 89B cytogenetic position, highlighting a possible major role for this chromosome position during the evolution of species specific adaptations to postmating prezygotic reproductive challenges.

  19. Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging.

    Johansson, Fredrik K; Brodd, Josefin; Eklöf, Charlotta; Ferletta, Maria; Hesselager, Göran; Tiger, Carl-Fredrik; Uhrbom, Lene; Westermark, Bengt

    2004-08-01

    Murine retroviruses may cause malignant tumors in mice by insertional mutagenesis of host genes. The use of retroviral tagging as a means of identifying cancer-causing genes has, however, almost entirely been restricted to hematopoietic tumors. The aim of this study was to develop a system allowing for the retroviral tagging of candidate genes in malignant brain tumors. Mouse gliomas were induced by a recombinant Moloney murine leukemia virus encoding platelet-derived growth factor (PDGF) B-chain. The underlying idea was that tumors evolve through a combination of PDGF-mediated autocrine growth stimulation and insertional mutagenesis of genes that cooperate with PDGF in gliomagenesis. Common insertion sites (loci that were tagged in more than one tumor) were identified by cloning and sequencing retroviral flanking segments, followed by blast searches of mouse genome databases. A number of candidate brain tumor loci (Btls) were identified. Several of these Btls correspond to known tumor-causing genes; these findings strongly support the underlying idea of our experimental approach. Other Btls harbor genes with a hitherto unproven role in transformation or oncogenesis. Our findings indicate that retroviral tagging with a growth factor-encoding virus may be a powerful means of identifying candidate tumor-causing genes in nonhematopoietic tumors. PMID:15273287

  20. Analysis of breast cancer metastasis candidate genes from next generation-sequencing via systematic functional genomics

    Blomstrøm, Monica Marie

    2016-01-01

    ) and non-CSCs. The main goal of this project was to functionally characterize a set of candidate genes recovered from next-generation sequencing analysis for their role in breast cancer metastasis formation. The starting gene set comprised 104 gene variants; i.e. 57 wildtype and 47 mutated variants....... During the project, the aim was to generate a panel of genetically identical (“isogenic”) MCF7 breast cancer cell lines with inducible overexpression of the gene variants, and to analyze these for effects on breast cancer growth and invasion in vitro under standardized conditions. Moreover, it was aimed...

  1. Pharmacogenetic effects of 'candidate gene complexes' on stroke in the GenHAT study

    Sørensen, Izel F; Vazquez, Ana I; Irvin, Marguerite R;

    2014-01-01

    Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP...... level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein...... groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene...

  2. Candidate gene study to investigate the genetic determinants of normal variation in central corneal thickness

    Dimasi, David P.; Kathryn P Burdon; Hewitt, Alex W; Savarirayan, Ravi; Healey, Paul R.; Mitchell, Paul; Mackey, David A.; Craig, Jamie E

    2010-01-01

    Purpose The genetic component underlying variation in central corneal thickness (CCT) in the normal population remains largely unknown. As CCT is an identified risk factor for open-angle glaucoma, understanding the genes involved in CCT determination could improve our understanding of the mechanisms involved in this association. Methods To identify novel CCT genes, we selected eight different candidates based on a range of criteria. These included; aquaporin 1 (AQ1), aquaporin 5 (AQ5), decori...

  3. Physiological and molecular characterization of drought responses and identification of candidate tolerance genes in cassava

    Turyagyenda, Laban F.; Kizito, Elizabeth B.; Ferguson, Morag; Baguma, Yona; Agaba, Morris; Jagger J W Harvey; Osiru, David S. O.

    2013-01-01

    Cassava is an important root crop to resource-poor farmers in marginal areas, where its production faces drought stress constraints. Given the difficulties associated with cassava breeding, a molecular understanding of drought tolerance in cassava will help in the identification of markers for use in marker-assisted selection and genes for transgenic improvement of drought tolerance. This study was carried out to identify candidate drought-tolerance genes and expression-based markers of droug...

  4. No association of candidate genes with cannabis use in a large sample of Australian twin families

    Verweij, C.J.H.; Zietsch, B.P.; Liu, J.Z.; Medland, S.E.; Lynskey, M.T.; Madden, P.A.F.; Agrawal, A.; Montgomery, G.W.; Heath, A.C.; Martin, N.G.

    2012-01-01

    While there is solid evidence that cannabis use is heritable, attempts to identify genetic influences at the molecular level have yielded mixed results. Here, a large twin family sample (n = 7452) was used to test for association between 10 previously reported candidate genes and lifetime frequency

  5. Bioinformatics-Driven Identification and Examination of Candidate Genes for Non-Alcoholic Fatty Liver Disease

    Banasik, Karina; Justesen, Johanne M.; Hornbak, Malene;

    2011-01-01

    Objective: Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. Research Design and Methods: By integrating public database text mining, trans-organism protein...

  6. Candidate fire blight resistance genes in Malus identified with the use of genomic tools and approaches

    The goal of this research is to utilize current advances in Rosaceae genomics to identify DNA markers for use in marker-assisted selection of durable resistance to fire blight. Candidate fire blight resistance genes were selected and ranked based upon differential expression after inoculation with ...

  7. Candidate genes for cross-resistance against DNA-damaging drugs

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D;

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA-dam...

  8. Mapping and expression of candidate genes for development rate in rainbow trout (Oncorhynchus mykiss)

    Development rate has important implications for many aspects of an individual's biology. In rainbow trout (Oncorhynchus mykiss), a major QTL for embryonic development rate has been detected on chromosome 5, but at present, few candidate genes have been mapped to this region. This paucity of known ge...

  9. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    David G Ashbrook

    2015-07-01

    Full Text Available Bipolar disorder (BD is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium’s bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis.We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1 and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG and TNR influence intercellular signaling in the striatum.

  10. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.

    Ashbrook, David G; Williams, Robert W; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  11. Gene Expression Analysis in Tubule Interstitial Compartments Reveals Candidate Agents for IgA Nephropathy

    Jinling Wang

    2014-09-01

    Full Text Available Background/Aims: Our aim was to explore the molecular mechanism underlying development of IgA nephropathy and discover candidate agents for IgA nephropathy. Methods: The differentially expressed genes (DEGs between patients with IgA nephropathy and normal controls were identified by the data of GSE35488 downloaded from GEO (Gene Expression Omnibus database. The co-expressed gene pairs among DEGs were screened to construct the gene-gene interaction network. Gene Ontology (GO enrichment analysis was performed to analyze the functions of DEGs. The biologically active small molecules capable of targeting IgA nephropathy were identified using the Connectivity Map (cMap database. Results: A total of 55 genes involved in response to organic substance, transcription factor activity and response to steroid hormone stimulus were identified to be differentially expressed in IgA nephropathy patients compared to healthy individuals. A network with 45 co-expressed gene pairs was constructed. DEGs in the network were significantly enriched in response to organic substance. Additionally, a group of small molecules were identified, such as doxorubicin and thapsigargin. Conclusion: Our work provided a systematic insight in understanding the mechanism of IgA nephropathy. Small molecules such as thapsigargin might be potential candidate agents for the treatment of IgA nephropathy.

  12. Investigation of the molecular relationship between breast cancer and obesity by candidate gene prioritization methods

    Saba Garshasbi

    2015-10-01

    Full Text Available Background: Cancer and obesity are two major public health concerns. More than 12 million cases of cancer are reported annually. Many reports confirmed obesity as a risk factor for cancer. The molecular relationship between obesity and breast cancer has not been clear yet. The purpose of this study was to investigate priorities of effective genes in the molecular relationship between obesity and breast cancer. Methods: In this study, computer simulation method was used for prioritizing the genes that involved in the molecular links between obesity and breast cancer in laboratory of systems biology and bioinformatics (LBB, Tehran University, Tehran, Iran, from March to July 2014. In this study, ENDEAVOUR software was used for prioritizing the genes and integrating multiple data sources was used for data analysis. Training genes were selected from effective genes in obesity and/or breast cancer. Two groups of candidate genes were selected. The first group was included the existential genes in 5 common region chromosomes (between obesity and breast cancer and the second group was included the results of genes microarray data analysis of research Creighton, et al (In 2012 on patients with breast cancer. The microarray data were analyzed with GER2 software (R online software on GEO website. Finally, both training and candidate genes were entered in ENDEAVOUR software package. Results: The candidate genes were prioritized to four style and five genes in ten of the first priorities were repeated twice. In other word, the outcome of prioritizing of 72 genes (Product of microarray data analysis and genes of 5 common chromosome regions (Between obesity and breast cancer showed, 5 genes (TNFRSF10B, F2, IGFALS, NTRK3 and HSP90B1 were the priorities in the molecular connection between obesity and breast cancer. Conclusion: There are some common genes between breast cancer and obesity. So, molecular relationship is confirmed. In this study the possible effect

  13. Evaluation of candidate reference genes for gene expression normalization in Brassica juncea using real time quantitative RT-PCR.

    Ruby Chandna

    Full Text Available The real time quantitative reverse transcription PCR (qRT-PCR is becoming increasingly important to gain insight into function of genes. Given the increased sensitivity, ease and reproducibility of qRT-PCR, the requirement of suitable reference genes for normalization has become important and stringent. It is now known that the expression of internal control genes in living organism vary considerably during developmental stages and under different experimental conditions. For economically important Brassica crops, only a couple of reference genes are reported till date. In this study, expression stability of 12 candidate reference genes including ACT2, ELFA, GAPDH, TUA, UBQ9 (traditional housekeeping genes, ACP, CAC, SNF, TIPS-41, TMD, TSB and ZNF (new candidate reference genes, in a diverse set of 49 tissue samples representing different developmental stages, stress and hormone treated conditions and cultivars of Brassica juncea has been validated. For the normalization of vegetative stages the ELFA, ACT2, CAC and TIPS-41 combination would be appropriate whereas TIPS-41 along with CAC would be suitable for normalization of reproductive stages. A combination of GAPDH, TUA, TIPS-41 and CAC were identified as the most suitable reference genes for total developmental stages. In various stress and hormone treated samples, UBQ9 and TIPS-41 had the most stable expression. Across five cultivars of B. juncea, the expression of CAC and TIPS-41 did not vary significantly and were identified as the most stably expressed reference genes. This study provides comprehensive information that the new reference genes selected herein performed better than the traditional housekeeping genes. The selection of most suitable reference genes depends on the experimental conditions, and is tissue and cultivar-specific. Further, to attain accuracy in the results more than one reference genes are necessary for normalization.

  14. Phylogenetic analyses of peanut resistance gene candidates and screening of different genotypes for polymorphic markers.

    Radwan, Osman E; Ahmed, Talaat A; Knapp, Steven J

    2010-01-01

    The nucleotide-binding-site-leucine-rich-repeat (NBS-LRR)-encoding gene family has attracted much research interest because approximately 75% of the plant disease resistance genes that have been cloned to date are from this gene family. Here, we describe a collection of peanut NBS-LRR resistance gene candidates (RGCs) isolated from peanut (Arachis) species by mining Gene Bank data base. NBS-LRR sequences assembled into TIR-NBS-LRR (75.4%) and non-TIR-NBS-LRR (24.6%) subfamilies. Total of 20 distinct clades were identified and showed a high level of sequence divergence within TIR-NBS and non-TIR-NBS subfamilies. Thirty-four primer pairs were designed from these RGC sequences and used for screening different genotypes belonging to wild and cultivated peanuts. Therefore, peanut RGC identified in this study will provide useful tools for developing DNA markers and cloning the genes for resistance to different pathogens in peanut. PMID:23961057

  15. QTLs and candidate genes for desiccation and abscisic acid content in maize kernels

    Charcosset Alain

    2010-01-01

    Full Text Available Abstract Background Kernel moisture at harvest is an important trait since a low value is required to prevent unexpected early germination and ensure seed preservation. It is also well known that early germination occurs in viviparous mutants, which are impaired in abscisic acid (ABA biosynthesis. To provide some insight into the genetic determinism of kernel desiccation in maize, quantitative trait loci (QTLs were detected for traits related to kernel moisture and ABA content in both embryo and endosperm during kernel desiccation. In parallel, the expression and mapping of genes involved in kernel desiccation and ABA biosynthesis, were examined to detect candidate genes. Results The use of an intermated recombinant inbred line population allowed for precise QTL mapping. For 29 traits examined in an unreplicated time course trial of days after pollination, a total of 78 QTLs were detected, 43 being related to kernel desiccation, 15 to kernel weight and 20 to ABA content. Multi QTL models explained 35 to 50% of the phenotypic variation for traits related to water status, indicating a large genetic control amenable to breeding. Ten of the 20 loci controlling ABA content colocated with previously detected QTLs controlling water status and ABA content in water stressed leaves. Mapping of candidate genes associated with kernel desiccation and ABA biosynthesis revealed several colocations between genes with putative functions and QTLs. Parallel investigation via RT-PCR experiments showed that the expression patterns of the ABA-responsive Rab17 and Rab28 genes as well as the late embryogenesis abundant Emb5 and aquaporin genes were related to desiccation rate and parental allele effect. Database searches led to the identification and mapping of two zeaxanthin epoxidase (ZEP and five novel 9-cis-epoxycarotenoid dioxygenase (NCED related genes, both gene families being involved in ABA biosynthesis. The expression of these genes appeared independent in

  16. ADHD: current and future therapeutics.

    Heal, David J; Smith, Sharon L; Findling, Robert L

    2012-01-01

    The stimulants, amphetamine and methylphenidate, have long been the mainstay of attention-deficit hyperactivity disorder (ADHD) therapy. They are rapidly effective and are generally the first medications selected by physicians. In the development of alternative pharmacological approaches, drug candidates have been evaluated with a wide diversity of mechanisms. All of these developments have contributed real progress in the field, but there is still much room for improvement and unmet clinical need in ADHD pharmacotherapy. The availability of a wide range of compounds with a high degree of specificity for individual monoamines (dopamine and noradrenaline) and/or different pharmacological mechanisms has refined our understanding of the essential elements for optimum pharmacological effect in managing ADHD. In this chapter, we review the pharmacology of the different classes of drug used to treat ADHD and provide a neurochemical rationale, predominantly from the use of in vivo microdialysis experiments, to explain their relative efficacy and potential to elicit side effects. In addition, we will consider how predictions based on results from animal models translate into clinical outcomes. The treatment of ADHD is also described from the perspective of the physician. Finally, the new research development for drugs to treat ADHD is discussed. PMID:21487953

  17. Genomic analysis reveals MATH gene(s) as candidate(s) for Plum pox virus (PPV) resistance in apricot (Prunus armeniaca L.).

    Zuriaga, Elena; Soriano, José Miguel; Zhebentyayeva, Tetyana; Romero, Carlos; Dardick, Chris; Cañizares, Joaquín; Badenes, Maria Luisa

    2013-09-01

    Sharka disease, caused by Plum pox virus (PPV), is the most important viral disease affecting Prunus species. A major PPV resistance locus (PPVres) has been mapped to the upper part of apricot (Prunus armeniaca) linkage group 1. In this study, a physical map of the PPVres locus in the PPV-resistant cultivar 'Goldrich' was constructed. Bacterial artificial chromosome (BAC) clones belonging to the resistant haplotype contig were sequenced using 454/GS-FLX Titanium technology. Concurrently, the whole genome of seven apricot varieties (three PPV-resistant and four PPV-susceptible) and two PPV-susceptible apricot relatives (P. sibirica var. davidiana and P. mume) were obtained using the Illumina-HiSeq2000 platform. Single nucleotide polymorphisms (SNPs) within the mapped interval, recorded from alignments against the peach genome, allowed us to narrow down the PPVres locus to a region of ∼196 kb. Searches for polymorphisms linked in coupling with the resistance led to the identification of 68 variants within 23 predicted transcripts according to peach genome annotation. Candidate resistance genes were ranked combining data from variant calling and predicted functions inferred from sequence homology. Together, the results suggest that members of a cluster of meprin and TRAF-C homology domain (MATHd)-containing proteins are the most likely candidate genes for PPV resistance in apricot. Interestingly, MATHd proteins are hypothesized to control long-distance movement (LDM) of potyviruses in Arabidopsis, and restriction for LDM is also a major component of PPV resistance in apricot. Although the PPV resistance gene(s) remains to be unambiguously identified, these results pave the way to the determination of the underlying mechanism and to the development of more accurate breeding strategies. PMID:23672686

  18. Utilization of Gene Mapping and Candidate Gene Mutation Screening for Diagnosing Clinically Equivocal Conditions:A Norrie Disease Case Study

    Vasiliki Chini; Danai Stambouli; Florina Mihaela Nedelea; George Alexandru Filipescu; Diana Mina; Marios Kambouris; Hatem El-Shanti

    2014-01-01

    Prenatal diagnosis was requested for an undiagnosed eye disease showing X-linked inheritance in a family. No medical records existed for the affected family members..Mapping of the X chromosome and candidate gene mutation screening i-dentified a c.C267A[p.F89L] mutation in NPD previously de-scribed as possibly causing Norrie disease..The detection of the c.C267A[p.F89L] variant in another unrelated family con-firms the pathogenic nature of the mutation for the Norrie dis-ease phenotype. Gene mapping, haplotype analysis, and can-didate gene screening have been previously utilized in research applications but were applied here in a diagnostic setting due to the scarcity of available clinical information..The clinical diagnosis and mutation identification were critical for provid-ing proper genetic counseling and prenatal diagnosis for this family.

  19. Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease.

    Karina Banasik

    Full Text Available OBJECTIVE: Candidate genes for non-alcoholic fatty liver disease (NAFLD identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes. RESEARCH DESIGN AND METHODS: By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D, central obesity, and WHO-defined metabolic syndrome (MetS. RESULTS: 273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05 to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations. CONCLUSIONS: Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.

  20. Evolutionary conservation of candidate osmoregulation genes in plant phloem sap-feeding insects.

    Jing, X; White, T A; Luan, J; Jiao, C; Fei, Z; Douglas, A E

    2016-06-01

    The high osmotic pressure generated by sugars in plant phloem sap is reduced in phloem-feeding aphids by sugar transformations and facilitated water flux in the gut. The genes mediating these osmoregulatory functions have been identified and validated empirically in the pea aphid Acyrthosiphon pisum: sucrase 1 (SUC1), a sucrase in glycoside hydrolase family 13 (GH13), and aquaporin 1 (AQP1), a member of the Drosophila integral protein (DRIP) family of aquaporins. Here, we describe molecular analysis of GH13 and AQP genes in phloem-feeding representatives of the four phloem-feeding groups: aphids (Myzus persicae), coccids (Planococcus citri), psyllids (Diaphorina citri, Bactericera cockerelli) and whiteflies (Bemisia tabaci MEAM1 and MED). A single candidate GH13-SUC gene and DRIP-AQP gene were identified in the genome/transcriptome of most insects tested by the criteria of sequence motif and gene expression in the gut. Exceptionally, the psyllid Ba. cockerelli transcriptome included a gut-expressed Pyrocoelia rufa integral protein (PRIP)-AQP, but has no DRIP-AQP transcripts, suggesting that PRIP-AQP is recruited for osmoregulatory function in this insect. This study indicates that phylogenetically related SUC and AQP genes may generally mediate osmoregulatory functions in these diverse phloem-feeding insects, and provides candidate genes for empirical validation and development as targets for osmotic disruption of pest species. PMID:26896054

  1. Network Based Integrated Analysis of Phenotype-Genotype Data for Prioritization of Candidate Symptom Genes

    Xing Li

    2014-01-01

    Full Text Available Background. Symptoms and signs (symptoms in brief are the essential clinical manifestations for individualized diagnosis and treatment in traditional Chinese medicine (TCM. To gain insights into the molecular mechanism of symptoms, we develop a computational approach to identify the candidate genes of symptoms. Methods. This paper presents a network-based approach for the integrated analysis of multiple phenotype-genotype data sources and the prediction of the prioritizing genes for the associated symptoms. The method first calculates the similarities between symptoms and diseases based on the symptom-disease relationships retrieved from the PubMed bibliographic database. Then the disease-gene associations and protein-protein interactions are utilized to construct a phenotype-genotype network. The PRINCE algorithm is finally used to rank the potential genes for the associated symptoms. Results. The proposed method gets reliable gene rank list with AUC (area under curve 0.616 in classification. Some novel genes like CALCA, ESR1, and MTHFR were predicted to be associated with headache symptoms, which are not recorded in the benchmark data set, but have been reported in recent published literatures. Conclusions. Our study demonstrated that by integrating phenotype-genotype relationships into a complex network framework it provides an effective approach to identify candidate genes of symptoms.

  2. Shared genetic influences on ADHD symptoms and very low-frequency EEG activity: a twin study

    Tye, C.; Rijsdijk, F.; Greven, C.U.; Kuntsi, J.; Asherson, P.; McLoughlin, G.

    2012-01-01

    BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex aetiology. The identification of candidate intermediate phenotypes that are both heritable and genetically linked to ADHD may facilitate the detection of susceptibi

  3. Retinoblastoma-associated protein 140 as a candidate for a novel etiological gene to hypertension.

    Crespo, Kimberley; Ménard, Annie; Deng, Alan Y

    2016-01-01

    Gene discovery in animal models may lead to the revelation of therapeutic targets for essential hypertension as well as mechanistic insights into blood pressure (BP) regulation. Our aim was to identify a disease-causing gene for a component of polygenic hypertension contrasting inbred hypertensive Dahl salt-sensitive (DSS) and normotensive Lewis rats. The chromosome segment harboring a quantitative trait locus (QTL), C16QTL, was first isolated from the rat genome via congenic strains. A candidate gene responsible for C16QTL causing a BP difference between DSS and Lewis rats was then identified using molecular analyses combining our independently-conducted total genome and gene-specific sequencings. The retinoblastoma-associated protein 140 (Rap140)/family with sequence similarity 208 member A (Fam208a) is the only candidate gene supported to be C16QTL among three genes in genome block 1 present in the C16QTL-residing interval. A mode of its actions could be to influence the expressions of genes that are downstream in a pathway potentially leading to BP regulation such as that encoding the solute carrier family 7 (cationic amino acid transporter, y+ system) member 12 (Slc7a12), which is specifically expressed in kidneys. Thus, Rap140/Fam208a probably encoding a transcription factor is the strongest candidate for a novel BP QTL that acts via a putative Rap140/Fam208a-Slc7a12-BP pathway. These data implicate a premier physiological role for Rap140/Fam208 beyond development and a first biological function for the Slc7a12 protein in any organism. PMID:27391979

  4. Transcriptomic Analysis Using Olive Varieties and Breeding Progenies Identifies Candidate Genes Involved in Plant Architecture

    González-Plaza, Juan J.; Ortiz-Martín, Inmaculada; Muñoz-Mérida, Antonio; García-López, Carmen; Sánchez-Sevilla, José F.; Luque, Francisco; Trelles, Oswaldo; Bejarano, Eduardo R.; De La Rosa, Raúl; Valpuesta, Victoriano; Beuzón, Carmen R.

    2016-01-01

    Plant architecture is a critical trait in fruit crops that can significantly influence yield, pruning, planting density and harvesting. Little is known about how plant architecture is genetically determined in olive, were most of the existing varieties are traditional with an architecture poorly suited for modern growing and harvesting systems. In the present study, we have carried out microarray analysis of meristematic tissue to compare expression profiles of olive varieties displaying differences in architecture, as well as seedlings from their cross pooled on the basis of their sharing architecture-related phenotypes. The microarray used, previously developed by our group has already been applied to identify candidates genes involved in regulating juvenile to adult transition in the shoot apex of seedlings. Varieties with distinct architecture phenotypes and individuals from segregating progenies displaying opposite architecture features were used to link phenotype to expression. Here, we identify 2252 differentially expressed genes (DEGs) associated to differences in plant architecture. Microarray results were validated by quantitative RT-PCR carried out on genes with functional annotation likely related to plant architecture. Twelve of these genes were further analyzed in individual seedlings of the corresponding pool. We also examined Arabidopsis mutants in putative orthologs of these targeted candidate genes, finding altered architecture for most of them. This supports a functional conservation between species and potential biological relevance of the candidate genes identified. This study is the first to identify genes associated to plant architecture in olive, and the results obtained could be of great help in future programs aimed at selecting phenotypes adapted to modern cultivation practices in this species. PMID:26973682

  5. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels.

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65-75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  6. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65–75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops.

  7. Identification of candidate genes for dissecting complex branch number trait in chickpea.

    Bajaj, Deepak; Upadhyaya, Hari D; Das, Shouvik; Kumar, Vinod; Gowda, C L L; Sharma, Shivali; Tyagi, Akhilesh K; Parida, Swarup K

    2016-04-01

    The present study exploited integrated genomics-assisted breeding strategy for genetic dissection of complex branch number quantitative trait in chickpea. Candidate gene-based association analysis in a branch number association panel was performed by utilizing the genotyping data of 401 SNP allelic variants mined from 27 known cloned branch number gene orthologs of chickpea. The genome-wide association study (GWAS) integrating both genome-wide GBS- (4556 SNPs) and candidate gene-based genotyping information of 4957 SNPs in a structured population of 60 sequenced desi and kabuli accessions (with 350-400kb LD decay), detected 11 significant genomic loci (genes) associated (41% combined PVE) with branch number in chickpea. Of these, seven branch number-associated genes were further validated successfully in two inter (ICC 4958×ICC 17160)- and intra (ICC 12299×ICC 8261)-specific mapping populations. The axillary meristem and shoot apical meristem-specific expression, including differential up- and down-regulation (4-5 fold) of the validated seven branch number-associated genes especially in high branch number as compared to the low branch number-containing parental accessions and homozygous individuals of two aforesaid mapping populations was apparent. Collectively, this combinatorial genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in seven potential known/candidate genes [PIN1 (PIN-FORMED protein 1), TB1 (teosinte branched 1), BA1/LAX1 (BARREN STALK1/LIKE AUXIN1), GRAS8 (gibberellic acid insensitive/GAI, Repressor of ga13/RGA and Scarecrow8/SCR8), ERF (ethylene-responsive element-binding factor), MAX2 (more axillary growth 2) and lipase] governing chickpea branch number. The useful information generated from this study have potential to expedite marker-assisted genetic enhancement by developing high-yielding cultivars with more number of productive (pods and seeds) branches in chickpea. PMID:26940492

  8. Coaching for ADHD

    Murphy, Kevin; Ratey, Nancy; Maynard, Sandy; Sussman, Susan; Wright, Sarah D.

    2010-01-01

    Despite limited scientific study on ADHD coaching as an intervention for adults with ADHD, the field of ADHD coaching has grown significantly and gained popularity in recent years. ADHD coaching is becoming a bona fide profession where one must advance through a rigorous training process, in order to be certified as a professional ADHD coach.…

  9. NK1 (TACR1) Receptor Gene ‘Knockout’ Mouse Phenotype Predicts Genetic Association with ADHD

    Yan, TC; McQuillin, A.; Thapar, A; Asherson, P.; Hunt, SP; Stanford, SC; Gurling, H.

    2010-01-01

    Mice with functional genetic ablation of the Tacr1 (substance P-preferring receptor) gene (NK1R−/−) are hyperactive. Here, we investigated whether this is mimicked by NK1R antagonism and whether dopaminergic transmission is disrupted in brain regions that govern motor performance. The locomotor activity of NK1R−/− and wild-type mice was compared after treatment with an NK1R antagonist and/or psychostimulant (d-amphetamine or methylphenidate). The inactivation of NK1R (by gene mutation or rece...

  10. Identification of two new drought specific candidate genes in sugarcane (Saccharum spp.

    Swapna Simon and G. Hemaprabha

    2010-07-01

    Full Text Available Effective identification and understanding of genes contribute to improve plant drought resistance. A study was conducted toidentify drought responsive candidate genes in sugarcane. Two genes viz., SOD (Superoxide dismutase and IGS (Indole 3-glycerol phosphate synthase were used as gene specific markers. Specific primers were designed based on the sequences inGenbank databases. Mapping population developed by crossing a drought tolerant parent (Co 740 and a drought susceptibleparent (Co 775 were phenotyped using physiological and sugar yield contributing parameters and were characterized into groupsof varying levels of resistance and susceptibility. Parental polymorphism for SOD and IGS specific primers was established usinggenomic DNA from field grown drought tolerant and susceptible parents, as the presence in Co 740 (resistant and absence in Co775 (susceptible respectively. Resistant and susceptible parents and six each resistant and susceptible progeny were subjected todrought imposition and RNA were isolated and RT - PCR analysis performed using these gene specific primers. A specific bandof 618 bp was identified in drought tolerant parent and progeny, absent in drought susceptible parent and progeny genotypedusing SOD gene. A specific band of 340 bp was identified in drought tolerant parent and progeny while it was absent in droughtsusceptible parent and progeny genotyped using IGS gene. These two fragments of interests were cloned in PTz57R/T vector andsequenced. SOD618 sequence was BLAST searched that showed 98 % homology with the drought inducible protein in Saccharumhybrid and IGS340 showed 80 % homology with the hypothetical protein expressed in rice genome. These new genes hold promiseimproving drought resistance of sugarcane through their use as candidate genes in marker assisted selection and in genetictransformation.

  11. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  12. Genetic relationships of some Citrus genotypes based on the candidate iron chlorosis genes

    KAÇAR, Yıldız AKA; Özhan ŞİMŞEK; DÖNMEZ, Dicle; BONCUK, Melda; YEŞİLOĞLU, Turgut; Ollitrault, Patrick

    2014-01-01

    Iron is one of the most important elements in plant mineral nutrition. Fe deficiency is a critical abiotic stress factor for Mediterranean citriculture; the development of marker-assisted selection for this trait would greatly enhance rootstock breeding. In this study, DNA sequencing and single-stranded conformation polymorphism (SSCP) analyses were performed to determine the allelic diversity of genes associated with tolerance to iron chlorosis in citrus. Two candidate iron chlorosis toleran...

  13. Tales of one gene discovery of a novel candidate receptor in mammalian taste

    Huang, Angela Lilly

    2007-01-01

    There are five basic taste modalities in mammals: bitter, sweet, sour, salty, and Umami (taste of MSG and L-amino acids). Receptors for bitter, sweet, and Umami were previously discovered. Identities of receptors for salty and sour taste modalities remained elusive. In this dissertation, I will present: 1) development of a novel bioinformatics screen to discover candidate receptors; 2) discovery of a novel gene, PKD2L1, in taste receptor cells; 3) evidence demonstrating PKD2L1-expressing tast...

  14. Genetic Analysis of Candidate Genes for the Metabolic Syndrome and Type 2 Diabetes

    Grallert, Harald

    2008-01-01

    This work investigated genetic susceptibility for type 2 diabetes and the metabolic syndrome (MetS) in several study designs. 31 DNA variants from 7 candidate genes involved in development of these diseases were analyzed for associations with the diseases or related parameters. Single nucleotide polymorphisms were genotyped using MALDI-TOF MS and statistically analyzed. The obtained associations are the basis for further functional studies, which will provide deeper insight in the etiology of...

  15. Attempted Replication of Reported Chronic Obstructive Pulmonary Disease Candidate Gene Associations

    Hersh, Craig P; DeMeo, Dawn L; Lange, Christoph; Litonjua, Augusto A.; Reilly, John J.; Kwiatkowski, David; Laird, Nan; Sylvia, Jody S.; Sparrow, David; Speizer, Frank E; Weiss, Scott T.; Silverman, Edwin K.

    2005-01-01

    Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or...

  16. Screening for candidate genes related to breast cancer with cDNA microarray analysis

    Yu-Juan Xiang; Zhi-Gang Yu; Ming-Ming Guo; Qin-Ye Fu; Zhong-Bing Ma; De-Zong Gao; Qiang Zhang; Yu-Yang Li; Liang Li; Lu Liu; Chun-Miao Ye

    2015-01-01

    Objective: The aim of this study was to reveal the exact changes during the occurrence of breast cancer to explore significant new and promising genes or factors related to this disease. Methods: We compared the gene expression profiles of breast cancer tissues with its uninvolved normal breast tissues as controls using the cDNA microarray analysis in seven breast cancer patients. Further, one representative gene, named IFI30, was quanti-tatively analyzed by real-time PCR to confirm the result of the cDNA microarray analysis. Results: A total of 427 genes were identified with significantly differential expression, 221 genes were up-regulated and 206 genes were down-regulated. And the result of cDNA microarray analysis was validated by detection of IFI30 mRNA level changes by real-time PCR. Genes for cell proliferation, cell cycle, cell division, mitosis, apoptosis, and immune response were enriched in the up-regulated genes, while genes for cell adhesion, proteolysis, and transport were significantly enriched in the down-regulated genes in breast cancer tissues compared with normal breast tissues by a gene ontology analysis. Conclusion: Our present study revealed a range of differentially expressed genes between breast cancer tissues and normal breast tissues, and provide candidate genes for further study focusing on the pathogenesis and new biomarkers for breast cancer. Copyright © 2015, Chinese Medical Association Production. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  17. Genetics of Estrogen-Related Traits; From Candidate Genes to GWAS

    Stolk, Lisette

    2009-01-01

    textabstractIn the first part of this thesis, the association of polymorphisms in three candidate genes (estrogen receptor alpha (ESR1), retinoblastoma interacting zinc finger domain (RIZ1) and catechol-O-methyltransferase (COMT)) with estradiol levels, age at natural menopause, BMD and fracture risk in the Rotterdam Study is shown. For the ESR1 gene, fine-mapping of the PvuII and XbaI LD-block is presented, together with a haplotype analysis, showing that one additional SNP in the promoter r...

  18. ADHD and Disruptive behavior scores – associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents

    Larsson Jan-Olov

    2008-04-01

    Full Text Available Abstract Background Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD and Disruptive Behavior Disorder (DBD. We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR. Methods A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL. Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes. Results We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD. In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD. In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior. Conclusion Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.

  19. Candidate gene association studies in syndromic and non-syndromic cleft lip and palate

    Daack-Hirsch, S.; Basart, A.; Frischmeyer, P. [Univ. of Iowa, IA (United States)] [and others

    1994-09-01

    Using ongoing case ascertainment through a birth defects registry, we have collected 219 nuclear families with non-syndromic cleft lip and/or palate and 111 families with a collection of syndromic forms. Syndromic cases include 24 with recognized forms and 72 with unrecognized syndromes. Candidate gene studies as well as genome-wide searches for evidence of microdeletions and isodisomy are currently being carried out. Candidate gene association studies, to date, have made use of PCR-based polymorphisms for TGFA, MSX1, CLPG13 (a CA repeat associated with a human homologue of a locus that results in craniofacial dysmorphogenesis in the mouse) and an STRP found in a Van der Woude syndrome microdeletion. Control tetranucleotide repeats, which insure that population-based differences are not responsible for any observed associations, are also tested. Studies of the syndromic cases have included the same list of candidate genes searching for evidence of microdeletions and a genome-wide search using tri- and tetranucleotide polymorphic markers to search for isodisomy or structural rearrangements. Significant associations have previously been identified for TGFA, and, in this report, identified for MSX1 and nonsyndromic cleft palate only (p = 0.04, uncorrected). Preliminary results of the genome-wide scan for isodisomy has returned no true positives and there has been no evidence for microdeletion cases.

  20. Transferability of microsatellite markers located in candidate genes for wood properties between Eucalyptus species

    Cintia V. Acuña

    2014-12-01

    Full Text Available Aim of study:  To analyze the feasibility of extrapolating conclusions on wood quality genetic control between different Eucalyptus species, particularly from species with better genomic information, to those less characterized. For this purpose, the first step is to analyze the conservation and cross-transferability of microsatellites markers (SSRs located in candidate genes.Area of study: Eucalyptus species implanted in Argentina coming from different Australian origins.Materials and methods: Twelve validated and polymorphic SSRs in candidate genes (SSR-CGs for wood quality in E. globulus were selected for cross species amplification in six species: E. grandis, E. saligna, E. dunnii, E. viminalis, E. camaldulensis and E. tereticornis.Main results: High cross-species transferability (92% to 100% was found for the 12 polymorphic SSRs detected in E. globulus. These markers revealed allelic diversity in nine important candidate genes: cinnamoyl CoA reductase (CCR, cellulose synthase 3 (CesA3, the transcription factor LIM1, homocysteine S-methyltransferase (HMT, shikimate kinase (SK, xyloglucan endotransglycosylase 2 (XTH2, glutathione S-transferase (GST, glutamate decarboxylase (GAD and peroxidase (PER.Research highlights: The markers described are potentially suitable for comparative QTL mapping, molecular marker assisted breeding (MAB and for population genetic studies across different species within the subgenus Symphyomyrtus.Keywords: validation; cross-transferability; SSR; functional markers; eucalypts; Symphyomyrtus.

  1. Quantitative transcription dynamic analysis reveals candidate genes and key regulators for ethanol tolerance in Saccharomyces cerevisiae

    Ma Menggen

    2010-06-01

    Full Text Available Abstract Background Derived from our lignocellulosic conversion inhibitor-tolerant yeast, we generated an ethanol-tolerant strain Saccharomyces cerevisiae NRRL Y-50316 by enforced evolutionary adaptation. Using a newly developed robust mRNA reference and a master equation unifying gene expression data analyses, we investigated comparative quantitative transcription dynamics of 175 genes selected from previous studies for an ethanol-tolerant yeast and its closely related parental strain. Results A highly fitted master equation was established and applied for quantitative gene expression analyses using pathway-based qRT-PCR array assays. The ethanol-tolerant Y-50316 displayed significantly enriched background of mRNA abundance for at least 35 genes without ethanol challenge compared with its parental strain Y-50049. Under the ethanol challenge, the tolerant Y-50316 responded in consistent expressions over time for numerous genes belonging to groups of heat shock proteins, trehalose metabolism, glycolysis, pentose phosphate pathway, fatty acid metabolism, amino acid biosynthesis, pleiotropic drug resistance gene family and transcription factors. The parental strain showed repressed expressions for many genes and was unable to withstand the ethanol stress and establish a viable culture and fermentation. The distinct expression dynamics between the two strains and their close association with cell growth, viability and ethanol fermentation profiles distinguished the tolerance-response from the stress-response in yeast under the ethanol challenge. At least 82 genes were identified as candidate and key genes for ethanol-tolerance and subsequent fermentation under the stress. Among which, 36 genes were newly recognized by the present study. Most of the ethanol-tolerance candidate genes were found to share protein binding motifs of transcription factors Msn4p/Msn2p, Yap1p, Hsf1p and Pdr1p/Pdr3p. Conclusion Enriched background of transcription abundance

  2. College Students with ADHD

    ... AACAP Facts for Families Guide Skip breadcrumb navigation College Students with ADHD Quick Links Facts For Families Guide ... with Attention Deficit Hyperactivity Disorder (ADHD) attend college. College students with ADHD face a number of challenges, including ...

  3. Getting Treatment for ADHD

    Full Text Available ... for your child. Medications Most children with ADHD benefit from taking medication. Medications do not cure ADHD. ... for side effects. A majority of children who benefit from medication for ADHD will continue to benefit ...

  4. Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes

    Santangelo Susan L

    2004-05-01

    Full Text Available Abstract Background A substantial body of research supports a genetic involvement in autism. Furthermore, results from various genomic screens implicate a region on chromosome 7q31 as harboring an autism susceptibility variant. We previously narrowed this 34 cM region to a 3 cM critical region (located between D7S496 and D7S2418 using the Collaborative Linkage Study of Autism (CLSA chromosome 7 linked families. This interval encompasses about 4.5 Mb of genomic DNA and encodes over fifty known and predicted genes. Four candidate genes (NRCAM, LRRN3, KIAA0716, and LAMB1 in this region were chosen for examination based on their proximity to the marker most consistently cosegregating with autism in these families (D7S1817, their tissue expression patterns, and likely biological relevance to autism. Methods Thirty-six intronic and exonic single nucleotide polymorphisms (SNPs and one microsatellite marker within and around these four candidate genes were genotyped in 30 chromosome 7q31 linked families. Multiple SNPs were used to provide as complete coverage as possible since linkage disequilibrium can vary dramatically across even very short distances within a gene. Analyses of these data used the Pedigree Disequilibrium Test for single markers and a multilocus likelihood ratio test. Results As expected, linkage disequilibrium occurred within each of these genes but we did not observe significant LD across genes. None of the polymorphisms in NRCAM, LRRN3, or KIAA0716 gave p LAMB1, the allelic association analysis revealed suggestive evidence for a positive association, including one individual SNP (p = 0.02 and three separate two-SNP haplotypes across the gene (p = 0.007, 0.012, and 0.012. Conclusions NRCAM, LRRN3, KIAA0716 are unlikely to be involved in autism. There is some evidence that variation in or near the LAMB1 gene may be involved in autism.

  5. Methylation profiling of 48 candidate genes in tumor and matched normal tissues from breast cancer patients.

    Li, Zibo; Guo, Xinwu; Wu, Yepeng; Li, Shengyun; Yan, Jinhua; Peng, Limin; Xiao, Zhi; Wang, Shouman; Deng, Zhongping; Dai, Lizhong; Yi, Wenjun; Xia, Kun; Tang, Lili; Wang, Jun

    2015-02-01

    Gene-specific methylation alterations in breast cancer have been suggested to occur early in tumorigenesis and have the potential to be used for early detection and prevention. The continuous increase in worldwide breast cancer incidences emphasizes the urgent need for identification of methylation biomarkers for early cancer detection and patient stratification. Using microfluidic PCR-based target enrichment and next-generation bisulfite sequencing technology, we analyzed methylation status of 48 candidate genes in paired tumor and normal tissues from 180 Chinese breast cancer patients. Analysis of the sequencing results showed 37 genes differentially methylated between tumor and matched normal tissues. Breast cancer samples with different clinicopathologic characteristics demonstrated distinct profiles of gene methylation. The methylation levels were significantly different between breast cancer subtypes, with basal-like and luminal B tumors having the lowest and the highest methylation levels, respectively. Six genes (ACADL, ADAMTSL1, CAV1, NPY, PTGS2, and RUNX3) showed significant differential methylation among the 4 breast cancer subtypes and also between the ER +/ER- tumors. Using unsupervised hierarchical clustering analysis, we identified a panel of 13 hypermethylated genes as candidate biomarkers that performed a high level of efficiency for cancer prediction. These 13 genes included CST6, DBC1, EGFR, GREM1, GSTP1, IGFBP3, PDGFRB, PPM1E, SFRP1, SFRP2, SOX17, TNFRSF10D, and WRN. Our results provide evidence that well-defined DNA methylation profiles enable breast cancer prediction and patient stratification. The novel gene panel might be a valuable biomarker for early detection of breast cancer. PMID:25636590

  6. The genetic basis of quality of life in healthy Swedish women: a candidate gene approach.

    Dounya Schoormans

    Full Text Available Quality of life (QoL is an increasingly important parameter in clinical practice as it predicts mortality and poor health outcomes. It is hypothesized that one may have a genetic predisposition for QoL. We therefore related 139 candidate genes, selected through a literature search, to QoL in healthy females.In 5,142 healthy females, background characteristics (i.e. demographic, clinical, lifestyle, and psychological factors were assessed. QoL was measured by the EORTC QLQ-C30, which consists of 15 domains. For all women genotype information was available. For each candidate gene, single nucleotide polymorphisms (SNPs were identified based on their functional (n = 2,663 and physical annotation (n = 10,649. SNPs were related to each QoL-domain, while controlling for background characteristics and population stratification. Finally, gene-based analyses were performed relating the combined effect of 10,649 SNPs (selected based on physical annotation for each gene, to QoL using the statistical software package VEGAS.Overall, we found no relation between genetic variations (SNPs and genes and 14 out of 15 QoL-domains. The strongest association was found between cognitive functioning and the top SNP rs1468951 (p = 1.21E-05 in the GSTZ1 gene. Furthermore, results of the gene-based test showed that the combined effect of 11 SNPs within the GSTZ1 gene is significantly associated with cognitive functioning (p = 2.60E-05.If validated, the involvement of GSTZ1 in cognitive functioning underscores its heritability which is likely the result of differences in the dopamine pathway, as GSTZ1 contributes to the equilibrium between dopamine and its neurotoxic metabolites via the glutathione redox cycle.

  7. Gene-level integrated metric of negative selection (GIMS prioritizes candidate genes for nephrotic syndrome.

    Matthew G Sampson

    Full Text Available Nephrotic syndrome (NS gene discovery efforts are now occurring in small kindreds and cohorts of sporadic cases. Power to identify causal variants in these groups beyond a statistical significance threshold is challenging due to small sample size and/or lack of family information. There is a need to develop novel methods to identify NS-associated variants. One way to determine putative functional relevance of a gene is to measure its strength of negative selection, as variants in genes under strong negative selection are more likely to be deleterious. We created a gene-level, integrated metric of negative selection (GIMS score for 20,079 genes by combining multiple comparative genomics and population genetics measures. To understand the utility of GIMS for NS gene discovery, we examined this score in a diverse set of NS-relevant gene sets. These included genes known to cause monogenic forms of NS in humans as well as genes expressed in the cells of the glomerulus and, particularly, the podocyte. We found strong negative selection in the following NS-relevant gene sets: (1 autosomal-dominant Mendelian focal segmental glomerulosclerosis (FSGS genes (p = 0.03 compared to reference, (2 glomerular expressed genes (p = 4×10(-23, and (3 predicted podocyte genes (p = 3×10(-9. Eight genes causing autosomal dominant forms of FSGS had a stronger combined score of negative selection and podocyte enrichment as compared to all other genes (p = 1 x 10(-3. As a whole, recessive FSGS genes were not enriched for negative selection. Thus, we also created a transcript-level, integrated metric of negative selection (TIMS to quantify negative selection on an isoform level. These revealed transcripts of known autosomal recessive disease-causing genes that were nonetheless under strong selection. We suggest that a filtering strategy that includes measuring negative selection on a gene or isoform level could aid in identifying NS-related genes. Our GIMS and TIMS

  8. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations

    Rajani Rai; Jong Joo Kim; Sanjeev Misra; Ashok Kumar; Balraj Mittal

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactio...

  9. Candidate gene analysis of GH1 for effects on growth and carcass composition of cattle.

    Taylor, J F; Coutinho, L L; Herring, K L; Gallagher, D S; Brenneman, R A; Burney, N; Sanders, J O; Turner, J W; Smith, S B; Miller, R K; Savell, J W; Davis, S K

    1998-06-01

    We present an approach to evaluate the support for candidate genes as quantitative trait loci (QTLs) within the context of genome-wide map-based cloning strategies. To establish candidacy, a bacterial artificial chromosome (BAC) clone containing a putative candidate gene is physically assigned to an anchored linkage map to localise the gene relative to an identified QTL effect. Microsatellite loci derived from BAC clones containing an established candidate gene are integrated into the linkage map facilitating the evaluation by interval analysis of the statistical support for QTL identity. Permutation analysis is employed to determine experiment-wise statistical support. The approach is illustrated for the growth hormone 1 (GH1) gene and growth and carcass phenotypes in cattle. Polymerase chain reaction (PCR) primers which amplify a 441 bp fragment of GH1 were used to systematically screen a bovine BAC library comprising 60,000 clones and with a 95% probability of containing a single copy sequence. The presence of GH1 in BAC-110R2C3 was confirmed by sequence analysis of the PCR product from this clone and by the physical assignment of BAC110R2C3 to bovine chromosome 19 (BTA19) band 22 by fluorescence in situ hybridisation (FISH). Microsatellite KHGH1 was isolated from BAC110R2C3 and scored in 529 reciprocal backcross and F2 fullsib progeny from 41 resource families derived from Angus (Bos taurus) and Brahman (Bos indicus). The microsatellite KHGH1 was incorporated into a framework genetic map of BTA19 comprising 12 microsatellite loci, the erythrocyte antigen T and a GH1-TaqI restriction fragment length polymorphism (RFLP). Interval analysis localised effects of taurus vs. indicus alleles on subcutaneous fat and the percentage of either extractable fat from the Iongissimus dorsi muscle to the region of BTA19 harbouring GH1. PMID:9720178

  10. Medical Sequencing of Candidate Genes for Nonsyndromic Cleft Lip and Palate.

    2005-12-01

    Full Text Available Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father. The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate. Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.

  11. Natural Genetic Variation and Candidate Genes for Morphological Traits in Drosophila melanogaster.

    Carreira, Valeria Paula; Mensch, Julián; Hasson, Esteban; Fanara, Juan José

    2016-01-01

    Body size is a complex character associated to several fitness related traits that vary within and between species as a consequence of environmental and genetic factors. Latitudinal and altitudinal clines for different morphological traits have been described in several species of Drosophila and previous work identified genomic regions associated with such variation in D. melanogaster. However, the genetic factors that orchestrate morphological variation have been barely studied. Here, our main objective was to investigate genetic variation for different morphological traits associated to the second chromosome in natural populations of D. melanogaster along latitudinal and altitudinal gradients in Argentina. Our results revealed weak clinal signals and a strong population effect on morphological variation. Moreover, most pairwise comparisons between populations were significant. Our study also showed important within-population genetic variation, which must be associated to the second chromosome, as the lines are otherwise genetically identical. Next, we examined the contribution of different candidate genes to natural variation for these traits. We performed quantitative complementation tests using a battery of lines bearing mutated alleles at candidate genes located in the second chromosome and six second chromosome substitution lines derived from natural populations which exhibited divergent phenotypes. Results of complementation tests revealed that natural variation at all candidate genes studied, invected, Fasciclin 3, toucan, Reticulon-like1, jing and CG14478, affects the studied characters, suggesting that they are Quantitative Trait Genes for morphological traits. Finally, the phenotypic patterns observed suggest that different alleles of each gene might contribute to natural variation for morphological traits. However, non-additive effects cannot be ruled out, as wild-derived strains differ at myriads of second chromosome loci that may interact

  12. Genome-wide linkage analysis of global gene expression in loin muscle tissue identifies candidate genes in pigs.

    Juan Pedro Steibel

    Full Text Available BACKGROUND: Nearly 6,000 QTL have been reported for 588 different traits in pigs, more than in any other livestock species. However, this effort has translated into only a few confirmed causative variants. A powerful strategy for revealing candidate genes involves expression QTL (eQTL mapping, where the mRNA abundance of a set of transcripts is used as the response variable for a QTL scan. METHODOLOGY/PRINCIPAL FINDINGS: We utilized a whole genome expression microarray and an F(2 pig resource population to conduct a global eQTL analysis in loin muscle tissue, and compared results to previously inferred phenotypic QTL (pQTL from the same experimental cross. We found 62 unique eQTL (FDR <10% and identified 3 gene networks enriched with genes subject to genetic control involved in lipid metabolism, DNA replication, and cell cycle regulation. We observed strong evidence of local regulation (40 out of 59 eQTL with known genomic position and compared these eQTL to pQTL to help identify potential candidate genes. Among the interesting associations, we found aldo-keto reductase 7A2 (AKR7A2 and thioredoxin domain containing 12 (TXNDC12 eQTL that are part of a network associated with lipid metabolism and in turn overlap with pQTL regions for marbling, % intramuscular fat (% fat and loin muscle area on Sus scrofa (SSC chromosome 6. Additionally, we report 13 genomic regions with overlapping eQTL and pQTL involving 14 local eQTL. CONCLUSIONS/SIGNIFICANCE: Results of this analysis provide novel candidate genes for important complex pig phenotypes.

  13. DGAT1, a new positional and functional candidate gene for intramuscular fat deposition in cattle.

    Thaller, G; Kühn, C; Winter, A; Ewald, G; Bellmann, O; Wegner, J; Zühlke, H; Fries, R

    2003-10-01

    Intramuscular fat content, also assessed as marbling of meat, represents an important beef quality trait. Recent work has mapped a quantitative trait locus (QTL) with an effect on marbling to the centromeric region of bovine chromosome 14, with the gene encoding thyroglobulin (TG) being proposed as a positional and functional candidate gene for this QTL. Recently, the gene encoding diacylglycerol O-acyltransferase (DGAT1), which also has been mapped within the region of the marbling QTL, has been demonstrated to affect the fat content of milk. In the present study, the effects of a 5'-polymorphism of TG and of a lysine/alanine polymorphism of DGAT1 on the fat content of musculus (m.) semitendinosus and m. longissimus dorsi in 55 bovine animals (28 German Holstein and 27 Charolais) has been investigated. Significant effects were found for both candidate genes in both the breeds. These effects seem to be independent of one another because the alleles of the two polymorphisms showed no statistically significant disequilibrium. The DGAT1 effect is mainly on the m. semitendinosus. The TG polymorphism only affects m. longissimus dorsi. However, both intramuscular fat enhancing effects seem to be recessive. The possibility of two linked loci, acting recessively on intramuscular fat content, will require special strategies when selecting for higher marbling scores. PMID:14510671

  14. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes.

    Saunders, Colleen J; Jalali Sefid Dashti, Mahjoubeh; Gamieldien, Junaid

    2016-01-01

    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation of human genes and identify candidate genes by ontology-seeded queries capturing the features of tendinopathy. Our BioOntological Relationship Graph database (BORG) integrates multiple sources of genomic and biomedical knowledge into an on-disk semantic network where human genes and their orthologs in mouse and rat are central concepts mapped to ontology terms. The BORG was used to screen all human genes for potential links to tendinopathy. Following further prioritisation, four strong candidate genes (COL11A2, ELN, ITGB3, LOX) were identified. These genes are differentially expressed in tendinopathy, functionally linked to features of tendinopathy and previously implicated in other connective tissue diseases. In conclusion, cross-domain semantic integration of multiple sources of biomedical knowledge, and interrogation of phenotypes and gene functions associated with disease, may significantly increase the probability of identifying strong and unobvious candidate genes in genetic association studies. PMID:26804977

  15. Targeting 160 candidate genes for blood pressure regulation with a genome-wide genotyping array.

    Siim Sõber

    Full Text Available The outcome of Genome-Wide Association Studies (GWAS has challenged the field of blood pressure (BP genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany to address (i SNP coverage in 160 BP candidate genes; (ii the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region+/-10 kb covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11 to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15 x 10(-5, the strength of some detected associations was close to this level: rs10889553 (LEPR and systolic BP (SBP (P = 4.5 x 10(-5 as well as rs10954174 (LEP and diastolic BP (DBP (P = 5.20 x 10(-5. In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1 revealed considerable association (P<10(-3 either with SBP, DBP, and/or hypertension (HYP. None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT. However, supportive evidence for the association of rs10889553 (LEPR and rs11195419 (ADRA2A with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.

  16. Identification of quantitative trait loci and candidate genes for cadmium tolerance in Populus

    Induri, Brahma R [West Virginia University; Ellis, Danielle R [West Virginia University; Slavov, Goncho T. [West Virginia University; Yin, Tongming [ORNL; Zhang, Xinye [ORNL; Tuskan, Gerald A [ORNL; DiFazio, Steven P [West Virginia University

    2012-01-01

    Understanding genetic variation for the response of Populus to heavy metals like cadmium (Cd) is an important step in elucidating the underlying mechanisms of tolerance. In this study, a pseudo-backcross pedigree of Populus trichocarpa Torr. & Gray and Populus deltoides Bart. was characterized for growth and performance traits after Cd exposure. A total of 16 quantitative trait loci (QTL) at logarithm of odds (LOD) ratio 2.5 were detected for total dry weight, its components and root volume. Major QTL for Cd responses were mapped to two different linkage groups and the relative allelic effects were in opposing directions on the two chromosomes, suggesting differential mechanisms at these two loci. The phenotypic variance explained by Cd QTL ranged from 5.9 to 11.6% and averaged 8.2% across all QTL. A whole-genome microarray study led to the identification of nine Cd-responsive genes from these QTL. Promising candidates for Cd tolerance include an NHL repeat membrane-spanning protein, a metal transporter and a putative transcription factor. Additional candidates in the QTL intervals include a putative homolog of a glutamate cysteine ligase, and a glutathione-S-transferase. Functional characterization of these candidate genes should enhance our understanding of Cd metabolism and transport and phytoremediation capabilities of Populus.

  17. Fine mapping and single nucleotide polymorphism association results of candidate genes for asthma and related phenotypes.

    Immervoll, T; Loesgen, S; Dütsch, G; Gohlke, H; Herbon, N; Klugbauer, S; Dempfle, A; Bickeböller, H; Becker-Follmann, J; Rüschendorf, F; Saar, K; Reis, A; Wichmann, H E; Wjst, M

    2001-10-01

    Several genome-wide screens for asthma and related phenotypes have been published to date but data on fine-mapping are scarce. For higher resolution we performed a fine-mapping study with 2 cM average spacing in often discussed asthma candidate regions (2p, 5q, 6p, 7p, 9q, 11p, and 12q) to narrow down the regions of interest. All participants of a Caucasian family study (97 families with at least two affected sib pairs) were genotyped for 49 supplementary polymorphic dinucleotide markers. Our results indicate increased evidence for linkage on chromosome 6p, 9q, and 12q. These candidate regions were further analyzed with SNP polymorphisms in the endothelin 1 (EDN1), lymphotoxin alpha (LTA), and neuronal nitric oxide synthase (NOS1) genes. In addition, IL4 -590C>T and IL10 -592C>A, localized on chromosomes 5q and 1q, respectively, have been analyzed for SNP association. Of the six SNPs tested, four revealed weak association with the examined phenotypes. These are the IL10 -592C>A SNP in the interleukin 10 gene (p=0.036 for eosinophil cell counts), the 4124T>C SNP in EDN1 (p=0.044 for asthma), the 3391C>T SNP in NOS1 with eosinophil cell counts (p=0.0086), and the 5266C>T polymorphism, also in the NOS1 gene, for high IgE levels (p=0.022). In summary, fine mapping data enable us to confine asthma candidate regions, while variants of EDN1 and NOS1, or nearby genes, may play an important role in this context. PMID:11668616

  18. Candidate gene expression affects intramuscular fat content and fatty acid composition in pigs.

    Wang, Wei; Xue, Wenda; Jin, Bangquan; Zhang, Xixia; Ma, Fei; Xu, Xiaofeng

    2013-02-01

    The objective of this study was to correlate the expression pattern of candidate genes with the intramuscular fat (IMF) content and fatty acid composition of the Longissimus dorsi muscle of Duroc × Shanzhu commercial crossbred pigs. Animals of both sexes were slaughtered at a body weight of about 90 kg. The IMF content and fatty acid composition of the Longissimus dorsi muscle were measured and correlated with candidate genes mRNA expression (AdPLA, ADRB3, LEPR, MC4R, PPARγ, PPARα, LPL, PEPCK, and SCD). Females presented higher IMF content (p < 0.05) than males. The total saturated fatty acid (SFA) in males was greater (p < 0.01), whereas the total monounsaturated fatty acid (MUFA) (p < 0.01) and polyunsaturated fatty acid (PUFA) (p < 0.05) were lower than in females. The expressions of AdPLA, MC4R, PEPCK, and SCD correlated with the IMF content (p < 0.05). AdPLA showed a positive association with MUFA and a negative association with SFA (p < 0.05). LEPR and MC4R were both positively and significantly associated with C18:3 and C20:0 (p < 0.05). PPARα and PPARγ were negatively correlated with SFA, and PPARγ was positively associated with MUFA (p < 0.05). LPL was positively associated with MUFA and negatively associated with SFA (p < 0.05). PEPCK was negatively correlated with PUFA (p < 0.05). SCD was positively associated with MUFA (p < 0.05). The revealed correlations may confirm that these candidate genes are important for fat deposition and fatty acid composition in pigs, and the evaluation and use of these genes may be useful for improving porcine meat quality. PMID:23275256

  19. Candidate gene analysis using imputed genotypes: cell cycle single-nucleotide polymorphisms and ovarian cancer risk

    Goode, Ellen L; Fridley, Brooke L; Vierkant, Robert A;

    2009-01-01

    existing genotype data, we conducted a combined analysis of five independent studies of invasive epithelial ovarian cancer. Up to 2,120 cases and 3,382 controls were genotyped in the course of two collaborations at a variety of SNPs in 11 cell cycle genes (CDKN2C, CDKN1A, CCND3, CCND1, CCND2, CDKN1B, CDK2......, rs649392, and rs3212891; CDK2 rs2069391, rs2069414, and rs17528736; and CCNE1 rs3218036. These results exemplify the utility of imputation in candidate gene studies and lend evidence to a role of cell cycle genes in ovarian cancer etiology, suggest a reduced set of SNPs to target in additional cases...

  20. Expression analysis of 13 ovine immune response candidate genes in Visna/Maedi disease progression.

    Larruskain, Amaia; Bernales, Irantzu; Luján, Lluis; de Andrés, Damián; Amorena, Beatriz; Jugo, Begoña M

    2013-07-01

    Visna/Maedi virus (VMV) is a lentivirus that infects cells of the monocyte/macrophage lineage in sheep. Infection with VMV may lead to Visna/Maedi (VM) disease, which causes a multisystemic inflammatory disorder causing pneumonia, encephalitis, mastitis and arthritis. The role of ovine immune response genes in the development of VM disease is not fully understood. In this work, sheep of the Rasa Aragonesa breed were divided into two groups depending on the presence/absence of VM-characteristic clinical lesions in the aforementioned organs and the relative levels of candidate gene expression, including cytokines and innate immunity loci were measured by qPCR in the lung and udder. Sheep with lung lesions showed differential expression in five target genes: CCR5, TLR7, and TLR8 were up regulated and IL2 and TNFα down regulated. TNFα up regulation was detected in the udder. PMID:23582860

  1. Candidate gene linkage approach to identify DNA variants that predispose to preterm birth

    Bream, Elise N A; Leppellere, Cara R; Cooper, Margaret E;

    2013-01-01

    Background:The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach.Methods:We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were...... used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses.Results:Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four...... through the infant and/or the mother in the etiology of PTB....

  2. Candidate genes associated with bud dormancy release in blackcurrant (Ribes nigrum L.

    Hedley Peter E

    2010-09-01

    Full Text Available Abstract Background The detrimental effects of mild winter temperatures on the consistency of cropping of blackcurrant (Ribes nigrum L. in parts of Europe have led to increasing interest in the genetic control of dormancy release in this species. This study examined patterns of gene expression in leaf buds of blackcurrant to identify key differential changes in these profiles around the time of budbreak. Results Using leaf bud tissue of blackcurrant, a cDNA library was generated as a source of blackcurrant ESTs for construction of a custom microarray, which was used to identify differential gene expression during dormancy release. Gene activity was lowest in early stages of dormancy, increasing to reach a maximum around the time of budbreak. Genes with significantly changing expression profiles were clustered and evidence is provided for the transient activity of genes previously associated with dormancy processes in other species. Expression profiling identified candidate genes which were mapped onto a blackcurrant genetic linkage map containing budbreak-related QTL. Three genes, which putatively encode calmodulin-binding protein, beta tubulin and acetyl CoA carboxylase respectively, were found to co-localise with budbreak QTL. Conclusions This study provides insight into the genetic control of dormancy transition in blackcurrant, identifying key changes in gene expression around budbreak. Genetic mapping of ESTs enabled the identification of genes which co-localise with previously-characterised blackcurrant QTL, and it is concluded that these genes have probable roles in release of dormancy and can therefore provide a basis for the development of genetic markers for future breeding deployment.

  3. Molecular Mapping and Candidate Gene Analysis for Numerous Spines on the Fruit of Cucumber.

    Zhang, Shengping; Liu, Shulin; Miao, Han; Wang, Min; Liu, Panna; Wehner, Todd C; Gu, Xingfang

    2016-09-01

    Number of spines on the fruit is an important quality trait in cucumber. The inheritance and identification of molecular markers for fruit spine density gene can provide a basis for breeding and lay the foundation for gene cloning. Cucumber inbred lines NCG-122 with numerous spines and NCG-121 with few spines were used for genetic analysis and gene mapping in this study. Genetic analysis showed that the numerous spines trait in NCG-122 was qualitative, and a single recessive nuclear gene (ns) controlled this trait. The few spines trait was dominant over the numerous spines trait. In the preliminary genetic mapping of the ns gene, 8 SSR markers were found to be linked to ns, which mapped to chromosome 2 (Chr.2) of cucumber. The closest flanking markers SSR22338 and SSR11596 were linked to the ns gene, with genetic distances of 10.2 and 1.7cM, respectively. One-hundred and thirty pairs of new SSR primers and 28 pairs of Indel primers were developed based on sequence information in the preliminary mapping region of ns Fifteen SSR markers and 2 Indel markers were identified to be linked to the ns gene after analysis on the F2 mapping population using the new molecular markers. The 2 closest flanking markers, SSRns-127 and SSR04219, were 0.7 and 2.4 cM from ns, respectively. The physical distance between SSRns-127 and SSR04219 was 266.1kb, containing 27 predicted genes. Csa2G285390 was speculated as the probable candidate gene for numerous spines. The accuracy of the closest linked marker to the ns gene, SSRns-127, for MAS breeding was 95.0%. PMID:27317924

  4. A Multiple Interaction Analysis Reveals ADRB3 as a Potential Candidate for Gallbladder Cancer Predisposition via a Complex Interaction with Other Candidate Gene Variations.

    Rai, Rajani; Kim, Jong Joo; Misra, Sanjeev; Kumar, Ashok; Mittal, Balraj

    2015-01-01

    Gallbladder cancer is the most common and a highly aggressive biliary tract malignancy with a dismal outcome. The pathogenesis of the disease is multifactorial, comprising the combined effect of multiple genetic variations of mild consequence along with numerous dietary and environmental risk factors. Previously, we demonstrated the association of several candidate gene variations with GBC risk. In this study, we aimed to identify the combination of gene variants and their possible interactions contributing towards genetic susceptibility of GBC. Here, we performed Multifactor-Dimensionality Reduction (MDR) and Classification and Regression Tree Analysis (CRT) to investigate the gene-gene interactions and the combined effect of 14 SNPs in nine genes (DR4 (rs20576, rs6557634); FAS (rs2234767); FASL (rs763110); DCC (rs2229080, rs4078288, rs7504990, rs714); PSCA (rs2294008, rs2978974); ADRA2A (rs1801253); ADRB1 (rs1800544); ADRB3 (rs4994); CYP17 (rs2486758)) involved in various signaling pathways. Genotyping was accomplished by PCR-RFLP or Taqman allelic discrimination assays. SPSS software version 16.0 and MDR software version 2.0 were used for all the statistical analysis. Single locus investigation demonstrated significant association of DR4 (rs20576, rs6557634), DCC (rs714, rs2229080, rs4078288) and ADRB3 (rs4994) polymorphisms with GBC risk. MDR analysis revealed ADRB3 (rs4994) to be crucial candidate in GBC susceptibility that may act either alone (p ADRB3 rs4994 as candidate influencing GBC susceptibility. PMID:26602921

  5. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    Pangilinan, Faith

    2012-08-02

    AbstractBackgroundNeural tube defects (NTDs) are common birth defects (~1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that variants in additional folate\\/B12 pathway genes contribute to NTD risk.MethodsA tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate\\/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects.ResultsNearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003–0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing.ConclusionsTo our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the

  6. Meta-analysis and candidate gene mining of low-phosphorus tolerance in maize

    Hongwei Zhang; Mohammed Shalim Uddin; Cheng Zou; Chuanxiao Xie; Yunbi Xu; WenXue Li

    2014-01-01

    Plants with tolerance to low-phosphorus (P) can grow better under low-P conditions, and understanding of genetic mechanisms of low-P tolerance can not only facilitate identifying relevant genes but also help to develop low-P tolerant cultivars. QTL meta-analysis was conducted after a comprehensive review of the reports on QTL mapping for low-P tolerance-related traits in maize. Meta-analysis pro-duced 23 consensus QTL (cQTL), 17 of which located in similar chromosome regions to those previously reported to influence root traits. Meanwhile, candidate gene mining yielded 215 genes, 22 of which located in the cQTL regions. These 22 genes are homologous to 14 functionally character-ized genes that were found to participate in plant low-P tolerance, including genes encoding miR399s, Pi transporters and purple acid phosphatases. Four cQTL loci (cQTL2-1, cQTL5-3, cQTL6-2, and cQTL10-2) may play important roles for low-P tolerance because each contains more original QTL and has better consistency across previous reports.

  7. Identification and Evolutionary Analysis of Potential Candidate Genes in a Human Eating Disorder

    Mullegama, Saman; Wyckoff, Gerald J.

    2016-01-01

    The purpose of this study was to find genes linked with eating disorders and associated with both metabolic and neural systems. Our operating hypothesis was that there are genetic factors underlying some eating disorders resting in both those pathways. Specifically, we are interested in disorders that may rest in both sleep and metabolic function, generally called Night Eating Syndrome (NES). A meta-analysis of the Gene Expression Omnibus targeting the mammalian nervous system, sleep, and obesity studies was performed, yielding numerous genes of interest. Through a text-based analysis of the results, a number of potential candidate genes were identified. VGF, in particular, appeared to be relevant both to obesity and, broadly, to brain or neural development. VGF is a highly connected protein that interacts with numerous targets via proteolytically digested peptides. We examined VGF from an evolutionary perspective to determine whether other available evidence supported a role for the gene in human disease. We conclude that some of the already identified variants in VGF from human polymorphism studies may contribute to eating disorders and obesity. Our data suggest that there is enough evidence to warrant eGWAS and GWAS analysis of these genes in NES patients in a case-control study. PMID:27088090

  8. Back to the sea twice: identifying candidate plant genes for molecular evolution to marine life

    Reusch Thorsten BH

    2011-01-01

    Full Text Available Abstract Background Seagrasses are a polyphyletic group of monocotyledonous angiosperms that have adapted to a completely submerged lifestyle in marine waters. Here, we exploit two collections of expressed sequence tags (ESTs of two wide-spread and ecologically important seagrass species, the Mediterranean seagrass Posidonia oceanica (L. Delile and the eelgrass Zostera marina L., which have independently evolved from aquatic ancestors. This replicated, yet independent evolutionary history facilitates the identification of traits that may have evolved in parallel and are possible instrumental candidates for adaptation to a marine habitat. Results In our study, we provide the first quantitative perspective on molecular adaptations in two seagrass species. By constructing orthologous gene clusters shared between two seagrasses (Z. marina and P. oceanica and eight distantly related terrestrial angiosperm species, 51 genes could be identified with detection of positive selection along the seagrass branches of the phylogenetic tree. Characterization of these positively selected genes using KEGG pathways and the Gene Ontology uncovered that these genes are mostly involved in translation, metabolism, and photosynthesis. Conclusions These results provide first insights into which seagrass genes have diverged from their terrestrial counterparts via an initial aquatic stage characteristic of the order and to the derived fully-marine stage characteristic of seagrasses. We discuss how adaptive changes in these processes may have contributed to the evolution towards an aquatic and marine existence.

  9. Computational analysis of candidate disease genes and variants for Salt-sensitive hypertension in indigenous Southern Africans

    Tiffin, Nicki

    2010-09-27

    Multiple factors underlie susceptibility to essential hypertension, including a significant genetic and ethnic component, and environmental effects. Blood pressure response of hypertensive individuals to salt is heterogeneous, but salt sensitivity appears more prevalent in people of indigenous African origin. The underlying genetics of salt-sensitive hypertension, however, are poorly understood. In this study, computational methods including text- and data-mining have been used to select and prioritize candidate aetiological genes for salt-sensitive hypertension. Additionally, we have compared allele frequencies and copy number variation for single nucleotide polymorphisms in candidate genes between indigenous Southern African and Caucasian populations, with the aim of identifying candidate genes with significant variability between the population groups: identifying genetic variability between population groups can exploit ethnic differences in disease prevalence to aid with prioritisation of good candidate genes. Our top-ranking candidate genes include parathyroid hormone precursor (PTH) and type-1angiotensin II receptor (AGTR1). We propose that the candidate genes identified in this study warrant further investigation as potential aetiological genes for salt-sensitive hypertension. © 2010 Tiffin et al.

  10. Distilling a Visual Network of Retinitis Pigmentosa Gene-Protein Interactions to Uncover New Disease Candidates.

    Daniel Boloc

    Full Text Available Retinitis pigmentosa (RP is a highly heterogeneous genetic visual disorder with more than 70 known causative genes, some of them shared with other non-syndromic retinal dystrophies (e.g. Leber congenital amaurosis, LCA. The identification of RP genes has increased steadily during the last decade, and the 30% of the cases that still remain unassigned will soon decrease after the advent of exome/genome sequencing. A considerable amount of genetic and functional data on single RD genes and mutations has been gathered, but a comprehensive view of the RP genes and their interacting partners is still very fragmentary. This is the main gap that needs to be filled in order to understand how mutations relate to progressive blinding disorders and devise effective therapies.We have built an RP-specific network (RPGeNet by merging data from different sources: high-throughput data from BioGRID and STRING databases, manually curated data for interactions retrieved from iHOP, as well as interactions filtered out by syntactical parsing from up-to-date abstracts and full-text papers related to the RP research field. The paths emerging when known RP genes were used as baits over the whole interactome have been analysed, and the minimal number of connections among the RP genes and their close neighbors were distilled in order to simplify the search space.In contrast to the analysis of single isolated genes, finding the networks linking disease genes renders powerful etiopathological insights. We here provide an interactive interface, RPGeNet, for the molecular biologist to explore the network centered on the non-syndromic and syndromic RP and LCA causative genes. By integrating tissue-specific expression levels and phenotypic data on top of that network, a more comprehensive biological view will highlight key molecular players of retinal degeneration and unveil new RP disease candidates.

  11. Genomic analysis of differentiation between soil types reveals candidate genes for local adaptation in Arabidopsis lyrata.

    Thomas L Turner

    Full Text Available Serpentine soil, which is naturally high in heavy metal content and has low calcium to magnesium ratios, comprises a difficult environment for most plants. An impressive number of species are endemic to serpentine, and a wide range of non-endemic plant taxa have been shown to be locally adapted to these soils. Locating genomic polymorphisms which are differentiated between serpentine and non-serpentine populations would provide candidate loci for serpentine adaptation. We have used the Arabidopsis thaliana tiling array, which has 2.85 million probes throughout the genome, to measure genetic differentiation between populations of Arabidopsis lyrata growing on granitic soils and those growing on serpentinic soils. The significant overrepresentation of genes involved in ion transport and other functions provides a starting point for investigating the molecular basis of adaptation to soil ion content, water retention, and other ecologically and economically important variables. One gene in particular, calcium-exchanger 7, appears to be an excellent candidate gene for adaptation to low CaratioMg ratio in A. lyrata.

  12. Association study of candidate genes for susceptibility to schizophrenia and bipolar disorder on chromosome 22Q13

    Severinsen, Jacob; Binderup, Helle; Mors, Ole; Wang, August G; Vang, Maria; Murray, V; Muir, Walter; Mckee, I; Kruse, Torben A; Blackwood, Douglas HR; Ewald, Henrik; Børglum, Anders

    Chromosome 22q is suspected to harbor risk genes for schizophrenia as well as bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. In a recent study of distantly related patients from...... the Faroe Islands we have obtained evidence suggesting two regions on chromosome 22q13 to potentially harbor susceptibility genes for both schizophrenia and bipolar affective disorder. We have selected a number of candidate genes from these two regions for further analysis, including the neuro......-gene WKL1, in which a missense mutation recently has been suggested to cause catatonic schizophrenia in a German family. The selected candidate genes were analyzed by a combination of database search and direct sequencing in a subset of the patients from the Faroe Islands in order to identify SNPs in the...

  13. Linkage mapping of candidate genes for induce resistance and growth promotion by trichoderma koningiopsis (th003) in tomato solanum lycopersicum

    Induced systemic resistance (ISR) is a mechanism by which plants enhance defenses against any stress condition. ISR and growth promotion are enhanced when tomato (Solanum lycopersicum) is inoculated with several strains of Trichoderma ssp. this study aims to genetically map tomato candidate genes involved in ISR and growth promotion induced by the Colombian native isolate Trichoderma koningiopsis th003. Forty-nine candidate genes previously identified on tomato plants treated with th003 and T. hamatum T382 strains were evaluated for polymorphisms and 16 of them were integrated on the highly saturated genetic linkage map named TOMATO EXPEN 2000. The location of six unigenes was similar to the location of resistance gene analogs (RGAS), defense related ests and resistance QTLs previously reported, suggesting new possible candidates for these quantitative trait loci (QTL) regions. The candidate gene-markers may be used for future ISR or growth promotion assisted selection in tomato.

  14. LINKAGE MAPPING OF CANDIDATE GENES FOR INDUCED RESISTANCE AND GROWTH PROMOTION BY Trichoderma koningiopsis (Th003 IN TOMATO Solanum lycopersicum

    Cotes Prado Alba Marina

    2011-08-01

    Full Text Available Induced systemic resistance (ISR is a mechanism by which plants enhance defenses against any stress condition. ISR and growth promotion are enhanced when tomato (Solanum lycopersicum is inoculated with several strains of Trichoderma ssp. This study aims to genetically map tomato candidate genes involved in ISR and growth promotion induced by the Colombian native isolate Trichoderma koningiopsis Th003. Forty-nine candidate genes previously identified on tomato plants treated with Th003 and T. hamatum T382 strains were evaluated for polymorphisms and 16 of them were integrated on the highly saturated genetic linkage map named “TOMATO EXPEN 2000”. The location of six unigenes was similar to the location of resistance gene analogs (RGAs, defense related ESTs and resistance QTLs previously reported, suggesting new possible candidates for these quantitative trait loci (QTL regions. The candidate gene-markers may be used for future ISR or growth promotion assisted selection in tomato.

  15. ADHD Perspectives: Medicalization and ADHD Connectivity

    Wright, Gloria Sunnie

    2012-01-01

    Today's "ADHDscape" is no longer confined to images of fidgety children falling off classroom chairs. Trans-generational images flood popular culture, from "ADHD creator" with entrepreneurial style, to "ADHD troublemaker". Indeed, ADHD's enigmatic characteristics seem to apply as much to crying babies as to forgetful grannies. With the recent…

  16. Candidate Genes Involved in the Biosynthesis of Triterpenoid Saponins in Platycodon grandiflorum Identified by Transcriptome Analysis

    Ma, Chun-Hua; Gao, Zheng-Jie; Zhang, Jia-Jin; Zhang, Wei; Shao, Jian-Hui; Hai, Mei-Rong; Chen, Jun-Wen; Yang, Sheng-Chao; Zhang, Guang-Hui

    2016-01-01

    Background: Platycodon grandiflorum is the only species in the genus Platycodon of the family Campanulaceae, which has been traditionally used as a medicinal plant for its lung-heat-clearing, antitussive, and expectorant properties in China, Japanese, and Korean. Oleanane-type triterpenoid saponins were the main chemical components of P. grandiflorum and platycodin D was the abundant and main bioactive component, but little is known about their biosynthesis in plants. Hence, P. grandiflorum is an ideal medicinal plant for studying the biosynthesis of Oleanane-type saponins. In addition, the genomic information of this important herbal plant is unavailable. Principal findings: A total of 58,580,566 clean reads were obtained, which were assembled into 34,053 unigenes, with an average length of 936 bp and N50 of 1,661 bp by analyzing the transcriptome data of P. grandiflorum. Among these 34,053 unigenes, 22,409 unigenes (65.80%) were annotated based on the information available from public databases, including Nr, NCBI, Swiss-Prot, KOG, and KEGG. Furthermore, 21 candidate cytochrome P450 genes and 17 candidate UDP-glycosyltransferase genes most likely involved in triterpenoid saponins biosynthesis pathway were discovered from the transcriptome sequencing of P. grandiflorum. In addition, 10,626 SSRs were identified based on the transcriptome data, which would provide abundant candidates of molecular markers for genetic diversity and genetic map for this medicinal plant. Conclusion: The genomic data obtained from P. grandiflorum, especially the identification of putative genes involved in triterpenoid saponins biosynthesis pathway, will facilitate our understanding of the biosynthesis of triterpenoid saponins at molecular level. PMID:27242873

  17. Harvesting candidate genes responsible for serious adverse drug reactions from a chemical-protein interactome.

    Lun Yang

    2009-07-01

    Full Text Available Identifying genetic factors responsible for serious adverse drug reaction (SADR is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI, a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN: all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4, whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703 enhances the unexpected binding of abacavir to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes.

  18. Candidate genes involved in the biosynthesis of triterpenoid saponins in Platycodon grandiflorum identified by transcriptome analysis

    Chunhua eMa

    2016-05-01

    Full Text Available Background: Platycodon grandiflorum is the only species in the genus Platycodon of the family Campanulaceae, which has been traditionally used as a medicinal plant for its lung-heat-clearing, antitussive, and expectorant properties in China, Japanese and Korean. Oleanane-type triterpenoid saponins were the main chemical components of P. grandiflorum and platycodin D was the abundant and main bioactive component, but little is known about their biosynthesis in plants. Hence, P. grandiflorum is an ideal medicinal plant for studying the biosynthesis of Oleanane-type saponins. In addition, the genomic information of this important herbal plant is unavailable.Principal Findings:A total of 58,580,566 clean reads were obtained, which were assembled into 34,053 unigenes, with an average length of 936 bp and N50 of 1,661 bp by analyzing the transcriptome data of P. grandiflorum. Among these 34,053 unigenes, 22,409 unigenes (65.80% were annotated based on the information available from public databases, including Nr, NCBI, Swiss-Prot, KOG and KEGG. Furthermore, 21 candidate cytochrome P450 genes and 17 candidate UDP-glycosyltransferase genes most likely involved in triterpenoid saponins biosynthesis pathway were discovered from the transcriptome sequencing of P. grandiflorum. In addition, 10,626 SSRs were identified based on the transcriptome data, which would provide abundant candidates of molecular markers for genetic diversity and genetic map for this medicinal plant.Conclusion:The genomic data obtained from P. grandiflorum, especially the identification of putative genes involved in triterpenoid saponins biosynthesis pathway, will facilitate our understanding of the biosynthesis of triterpenoid saponins at molecular level.

  19. Dynamic QTL analysis and candidate gene mapping for waterlogging tolerance at maize seedling stage.

    Khalid A Osman

    Full Text Available Soil waterlogging is one of the major abiotic stresses adversely affecting maize growth and yield. To identify dynamic expression of genes or quantitative trait loci (QTL, QTL associated with plant height, root length, root dry weight, shoot dry weight and total dry weight were identified via conditional analysis in a mixed linear model and inclusive composite interval mapping method at three respective periods under waterlogging and control conditions. A total of 13, 19 and 23 QTL were detected at stages 3D|0D (the period during 0-3 d of waterlogging, 6D|3D and 9D|6D, respectively. The effects of each QTL were moderate and distributed over nine chromosomes, singly explaining 4.14-18.88% of the phenotypic variation. Six QTL (ph6-1, rl1-2, sdw4-1, sdw7-1, tdw4-1 and tdw7-1 were identified at two consistent stages of seedling development, which could reflect a continuous expression of genes; the remaining QTL were detected at only one stage. Thus, expression of most QTL was influenced by the developmental status. In order to provide additional evidence regarding the role of corresponding genes in waterlogging tolerance, mapping of Expressed Sequence Tags markers and microRNAs were conducted. Seven candidate genes were observed to co-localize with the identified QTL on chromosomes 1, 4, 6, 7 and 9, and may be important candidate genes for waterlogging tolerance. These results are a good starting point for understanding the genetic basis for selectively expressing of QTL in different stress periods and the common genetic control mechanism of the co-localized traits.

  20. Canine candidate genes for dilated cardiomyopathy: annotation of and polymorphic markers for 14 genes

    van Oost Bernard A

    2007-10-01

    Full Text Available Abstract Background Dilated cardiomyopathy is a myocardial disease occurring in humans and domestic animals and is characterized by dilatation of the left ventricle, reduced systolic function and increased sphericity of the left ventricle. Dilated cardiomyopathy has been observed in several, mostly large and giant, dog breeds, such as the Dobermann and the Great Dane. A number of genes have been identified, which are associated with dilated cardiomyopathy in the human, mouse and hamster. These genes mainly encode structural proteins of the cardiac myocyte. Results We present the annotation of, and marker development for, 14 of these genes of the dog genome, i.e. α-cardiac actin, caveolin 1, cysteine-rich protein 3, desmin, lamin A/C, LIM-domain binding factor 3, myosin heavy polypeptide 7, phospholamban, sarcoglycan δ, titin cap, α-tropomyosin, troponin I, troponin T and vinculin. A total of 33 Single Nucleotide Polymorphisms were identified for these canine genes and 11 polymorphic microsatellite repeats were developed. Conclusion The presented polymorphisms provide a tool to investigate the role of the corresponding genes in canine Dilated Cardiomyopathy by linkage analysis or association studies.

  1. Semantic interrogation of a multi knowledge domain ontological model of tendinopathy identifies four strong candidate risk genes

    Colleen J. Saunders; Mahjoubeh Jalali Sefid Dashti; Junaid Gamieldien

    2016-01-01

    Tendinopathy is a multifactorial syndrome characterised by tendon pain and thickening, and impaired performance during activity. Candidate gene association studies have identified genetic factors that contribute to intrinsic risk of developing tendinopathy upon exposure to extrinsic factors. Bioinformatics approaches that data-mine existing knowledge for biological relationships may assist with the identification of candidate genes. The aim of this study was to data-mine functional annotation...

  2. Expression studies of the obesity candidate gene FTO in pig

    Madsen, Majbritt Busk; Birck, Malene Muusfeldt; Fredholm, Merete;

    2010-01-01

    Obesity is an increasing problem worldwide and research on candidate genes in good animal models is highly needed. The pig is an excellent model as its metabolism, organ size, and eating habits resemble that of humans. The present study is focused on the characterization of the fat mass and obesity...... developmental stages. Expression of the FTO transcript was detected in all tissues tested with significantly higher levels in brain tissues (cortex, cerebellum, and hippocampus; P < 0.001). These levels varied through the development and between the specific parts of the brain studied (i.e., frontal cortex and...

  3. Evaluation of common genetic variants in 82 candidate genes as risk factors for neural tube defects

    Pangilinan Faith

    2012-08-01

    Full Text Available Abstract Background Neural tube defects (NTDs are common birth defects (~1 in 1000 pregnancies in the US and Europe that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T and MTHFD1 rs2236225 (R653Q have been found to increase NTD risk. We hypothesized that variants in additional folate/B12 pathway genes contribute to NTD risk. Methods A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents, including 301 cases and 341 Irish controls to perform case–control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Results Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury and included the known NTD risk factor MTHFD1 R653Q (rs2236225. The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 [1.23-2.08], p = 0.0003 for the minor allele. Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. Conclusions To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive

  4. Computational Systems for Selection and Priorization of Candidate Genes that Underlie Human Hereditary Disease

    Adášková, Jana

    Praha : Ústav informatiky AV ČR, v. v. i. & MATFYZPRESS, 2007 - (Hakl, F.), s. 2-7 ISBN 978-80-7378-019-7. [Doktorandské dny '07 Ústavu informatiky AV ČR, v. v. i.. Malá Úpa (CZ), 17.09.2007-19.09.2007] R&D Projects: GA MŠk(CZ) 1M06014 Institutional research plan: CEZ:AV0Z10300504 Keywords : candidate gene selection * priorization * data mining * text mining * human heredity disease Subject RIV: IN - Informatics, Computer Science

  5. Identification of Fat4 as a candidate tumor suppressor gene in breast cancers

    Qi, Chao; Zhu, Yiwei Tony; Hu, Liping; Zhu, Yi-Jun

    2009-01-01

    Fat, a candidate tumor suppressor in drosophila, is a component of Hippo signaling pathway involved in controlling organ size. We found that a ~3Mbp deletion in mouse chromosome 3 caused tumorigenesis of a non-tumorigenic mammary epithelial cell line. The expression of Fat4 gene, one member of the Fat family, in the deleted region was inactivated, which resulted from promoter methylation of another Fat4 allele following the deletion of one Fat4 allele. Re-expression of Fat4 in Fat4-deficient ...

  6. The Genetic Basis of Quality of Life in Healthy Swedish Women: A Candidate Gene Approach

    Dounya Schoormans; Jingmei Li; Hatef Darabi; Yvonne Brandberg; Sprangers, Mirjam A. G.; Mikael Eriksson; Zwinderman, Koos H.; Per Hall

    2015-01-01

    Background Quality of life (QoL) is an increasingly important parameter in clinical practice as it predicts mortality and poor health outcomes. It is hypothesized that one may have a genetic predisposition for QoL. We therefore related 139 candidate genes, selected through a literature search, to QoL in healthy females. Methods In 5,142 healthy females, background characteristics (i.e. demographic, clinical, lifestyle, and psychological factors) were assessed. QoL was measured by the EORTC QL...

  7. Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

    Mahfouz, Ahmed; Ziats, Mark N; Rennert, Owen M; Lelieveldt, Boudewijn P F; Reinders, Marcel J T

    2015-12-01

    Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function. PMID:26399424

  8. The norepinephrine transporter gene is a candidate gene for panic disorder

    Buttenschøn, H N; Kristensen, A S; Buch, H N;

    2011-01-01

    Panic disorder (PD) is an anxiety disorder characterized by recurrent panic attacks with a lifetime prevalence of 4.7%. Genetic factors are known to contribute to the development of the disorder. Several lines of evidence point towards a major role of the norepinephrine system in the pathogenesis...... of PD. The SLC6A2 gene is located on chromosome 16q12.2 and encodes the norepinephrine transporter (NET), responsible for the reuptake of norepinephrine into presynaptic nerve terminals. The aim of the present study was to analyze genetic variants located within the NET gene for association with PD...

  9. Identification of candidate target genes of pituitary adenomas based on the DNA microarray.

    Zhou, Wei; Ma, Chun-Xiao; Xing, Ya-Zhou; Yan, Zhao-Yue

    2016-03-01

    The present study aimed to explore molecular mechanisms involved in pituitary adenomas (PAs) and to discover target genes for their treatment. The gene expression profile GSE4488 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified using the Limma package and analyzed by two‑dimensional hierarchical clustering. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions of DEGs. Subsequently, the protein‑protein interaction (PPI) network was constructed using Cytoscape software. DEGs were then mapped to the connectivity map database to identify molecular agents associated with the underlying mechanisms of PAs. A total of 340 upregulated and 49 downregulated DEGs in PA samples compared with those in normal controls were identified. Hierarchical clustering analysis showed that DEGs were highly differentially expressed, indicating their aptness for distinguishing PA samples from normal controls. Significant gene ontology terms were positive regulation of immune system-associated processes for downregulated DEGs and skeletal system development for upregulated DEGs. Pathways significantly enriched by DEGs included extracellular matrix (ECM)‑receptor interaction, the Hedgehog (Hh) signaling pathway and neuroactive ligand‑receptor interaction. The PPI network was constructed with 117 nodes, 123 edges and CD44 and Gli2 as hub nodes. Furthermore, depudecin, a small molecule drug, was identified to be mechanistically associated with PA. The genes CD44 and Gli2 have important roles in the progression of PAs via ECM‑receptor interaction and the Hh signaling pathway and are therefore potential target genes of PA. In addition, depudecin may be a candidate drug for the treatment of PAs. PMID:26782791

  10. Co-localization of growth QTL with differentially expressed candidate genes in rainbow trout.

    Kocmarek, Andrea L; Ferguson, Moira M; Danzmann, Roy G

    2015-09-01

    We tested whether genes differentially expressed between large and small rainbow trout co-localized with familial QTL regions for body size. Eleven chromosomes, known from previous work to house QTL for weight and length in rainbow trout, were examined for QTL in half-sibling families produced in September (1 XY male and 1 XX neomale) and December (1 XY male). In previous studies, we identified 108 candidate genes for growth expressed in the liver and white muscle in a subset of the fish used in this study. These gene sequences were BLASTN aligned against the rainbow trout and stickleback genomes to determine their location (rainbow trout) and inferred location based on synteny with the stickleback genome. Across the progeny of all three males used in the study, 63.9% of the genes with differential expression appear to co-localize with the QTL regions on 6 of the 11 chromosomes tested in these males. Genes that co-localized with QTL in the mixed-sex offspring of the two XY males primarily showed up-regulation in the muscle of large fish and were related to muscle growth, metabolism, and the stress response. PMID:26360524

  11. POSITIONAL CANDIDATE GENE SELECTION FROM LIVESTOCK EST DATABASES USING GENE ONTOLOGY

    The number of expressed sequence tags (ESTs) in GenBank has now surpassed 200,000 for cattle and 100,000 for swine. The Institute of Genome Research (TIGR) has organized these sequences into approximately 60,000 non-redundant consensus sequences for cattle and 40,000 for swine in the TIGR Gene Indi...

  12. ADHD ja rentoutuminen : Rentoutusopas ADHD-liitolle

    Koskinen, Henna; Miettinen, Outi

    2016-01-01

    Opinnäytetyön tarkoitus oli tuottaa ADHD-liitolle opetuskäyttöön ja jaettavaksi rentoutusopas, jossa on kaikenikäisille rentoutumisvaihtoehtoja. Työ sai alkunsa suunnittelupalaverissa yhdessä ADHD-liiton kanssa. ADHD on aktiivisuuden ja tarkkaavuuden häiriö ja se on neuropsykiatrinen häiriö. ADHD:n ydinoireet ovat tarkkaamattomuus, yliaktiivisuus ja impulsiivisuus ja ne näkyvät sekä painottuvat eri tavoin ja haittaavat usealla elämän osa-alueella. Työssämme perehdytään ADHD:n etiologiaan,...

  13. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/.

  14. Detection of differentially expressed candidate genes for a fatty liver QTL on mouse chromosome 12

    Kobayashi, Misato; Suzuki, Miyako; Ohno, Tamio; Tsuzuki, Kana; Taguchi, Chie; Tateishi, Soushi; Kawada, Teruo; Kim, Young-Il; Murai, Atsushi; Horio, Fumihiko

    2016-01-01

    Background The SMXA-5 mouse is an animal model of high-fat diet-induced fatty liver. The major QTL for fatty liver, Fl1sa on chromosome 12, was identified in a SM/J × SMXA-5 intercross. The SMXA-5 genome consists of the SM/J and A/J genomes, and the A/J allele of Fl1sa is a fatty liver-susceptibility allele. The existence of the responsible genes for fatty liver within Fl1sa was confirmed in A/J-12SM consomic mice. The aim of this study was to identify candidate genes for Fl1sa, and to invest...

  15. Evaluation of nine candidate genes in patients with normal tension glaucoma: a case control study

    Reinthal Eva

    2009-09-01

    Full Text Available Abstract Background Normal tension glaucoma is a major subtype of glaucoma, associated with intraocular pressures that are within the statistically normal range of the population. Monogenic forms following classical inheritance patterns are rare in this glaucoma subtype. Instead, multigenic inheritance is proposed for the majority of cases. The present study tested common sequence variants in candidate genes for association with normal tension glaucoma in the German population. Methods Ninety-eight SNPs were selected to tag the common genetic variation in nine genes, namely OPTN (optineurin, RDX (radixin, SNX16 (sorting nexin 16, OPA1 (optic atrophy 1, MFN1 (mitofusin 1, MFN2 (mitofusin 2, PARL (presenilin associated, rhomboid-like, SOD2 (superoxide dismutase 2, mitochondrial and CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1. These SNPs were genotyped in 285 cases and 282 fully evaluated matched controls. Statistical analyses comprised single polymorphism association as well as haplogroup based association testing. Results Results suggested that genetic variation in five of the candidate genes (RDX, SNX16, OPA1, SOD2 and CYP1B1 is unlikely to confer major risk to develop normal tension glaucoma in the German population. In contrast, we observed a trend towards association of single SNPs in OPTN, MFN1, MFN2 and PARL. The SNPs of OPTN, MFN2 and PARL were further analysed by multimarker haplotype-based association testing. We identified a risk haplotype being more frequent in patients and a vice versa situation for the complementary protective haplotype in each of the three genes. Conclusion Common variants of OPTN, PARL, MFN1 and MFN2 should be analysed in other cohorts to confirm their involvement in normal tension glaucoma.

  16. Candidate genes of Waldenström’s macroglobulinemia: current evidence and research

    Bianchi G

    2013-07-01

    Full Text Available Giada Bianchi,1 Antonio Sacco,1 Shaji Kumar,2 Giuseppe Rossi,3 Irene Ghobrial,1 Aldo Roccaro11Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 2Division of Hematology, Mayo Clinic, Rochester, MN, USA; 3Department of Hematology, Spedali Civili di Brescia, Brescia, ItalyAbstract: Waldenström’s macroglobulinemia (WM is a relatively uncommon, indolent malignancy of immunoglobulin M-producing B cells. The World Health Organization classifies it as a lymphoplasmacytic lymphoma and patients typically present with anemia, hepatosplenomegaly and diffuse lymphadenopathies. Historically, the genetic characterization of the disease has been hampered by the relatively low proliferative rate of WM cells, thus making karyotyping challenging. The use of novel technologies such as fluorescence in situ hybridization, gene array, and whole genome sequencing has contributed greatly to establishing candidate genes in the pathophysiology of WM and to identifying potential treatment targets, such as L265P MYD88. The discovery of microRNAs and the recognition of epigenetics as a major modulatory mechanism of oncogene expression and/or oncosuppressor silencing have aided in further understanding the pathogenesis of WM. Once thought to closely resemble multiple myeloma, a cancer of terminally differentiated, immunoglobulin-secreting plasma cells, WM appears to genetically cluster with other indolent B-cell lymphomas such as chronic lymphocytic leukemia/small cell lymphoma. The relative high incidence of familial cases of WM and other B-cell malignancies has been helpful in identifying high-risk gene candidates. In this review, we focus on the established genes involved in the pathogenesis of WM, with special emphasis on the key role of derangement of the nuclear factor kappa B signaling pathway and epigenetic mechanisms.Keywords: genetics, familial cases, NF-κB, whole genome sequencing, MYD88

  17. A candidate-gene association study for berry colour and anthocyanin content in Vitis vinifera L.

    Silvana Cardoso

    Full Text Available Anthocyanin content is a trait of major interest in Vitis vinifera L. These compounds affect grape and wine quality, and have beneficial effects on human health. A candidate-gene approach was used to identify genetic variants associated with anthocyanin content in grape berries. A total of 445 polymorphisms were identified in 5 genes encoding transcription factors and 10 genes involved in either the biosynthetic pathway or transport of anthocyanins. A total of 124 SNPs were selected to examine association with a wide range of phenotypes based on RP-HPLC analysis and visual characterization. The phenotypes were total skin anthocyanin (TSA concentration but also specific types of anthocyanins and relative abundance. The visual assessment was based on OIV (Organisation Internationale de la Vigne et du Vin descriptors for berry and skin colour. The genes encoding the transcription factors MYB11, MYBCC and MYC(B were significantly associated with TSA concentration. UFGT and MRP were associated with several different types of anthocyanins. Skin and pulp colour were associated with nine genes (MYB11, MYBCC, MYC(B, UFGT, MRP, DFR, LDOX, CHI and GST. Pulp colour was associated with a similar group of 11 genes (MYB11, MYBCC, MYC(B, MYC(A, UFGT, MRP, GST, DFR, LDOX, CHI and CHS(A. Statistical interactions were observed between SNPs within the transcription factors MYB11, MYBCC and MYC(B. SNPs within LDOX interacted with MYB11 and MYC(B, while SNPs within CHI interacted with MYB11 only. Together, these findings suggest the involvement of these genes in anthocyanin content and on the regulation of anthocyanin biosynthesis. This work forms a benchmark for replication and functional studies.

  18. Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

    Xiaoyan Liu

    Full Text Available To investigate the relationship between amnestic mild cognitive impairment (aMCI and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G, to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT and to the tau hypothesis (MAPT/STH rs242562 GG in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD--those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

  19. Intraindividual variability (IIV in an animal model of ADHD - the Spontaneously Hypertensive Rat

    Sagvolden Terje

    2010-10-01

    Full Text Available Abstract Attention-deficit/hyperactivity disorder (ADHD is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously Hypertensive Rat (SHR/NCrl is an animal model of ADHD, expressing high activity, inattention and impulsive behavior during operant and task tests. The SHR might be useful for identifying genes for variability, but it is not known whether it also expresses high IIV, as is symptomatic of ADHD. We therefore conducted an investigation of IIV in the SHR. We used 16 SHR/NCrl rats and 15 Wistar-Kyoto (WKY/Nico controls applying a reinforcement schedule used in the validation of the SHR as an animal model of ADHD. We represented IIV as the average absolute deviation of individual behavior within the five 18-min segments of each experimental session from the average behavioral trait value within that session ('individual phenotypic dispersion', PDi. PDi for hyperactivity, impulsiveness and inattention in the SHR and WKY rats was analyzed using nonparametric ranking by experimental session. SHR/NCrl rats had higher PDi than WKY/Nico controls for impulsiveness and inattention. There was a significant upward trend for PDi over experimental segments within sessions for attention in SHR rats, but not in WKY. PDi for hyperactivity was correlated with PDi for impulsiveness and we therefore excluded observations associated with short IRTs (

  20. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies

    N. Johns; B. H. Tan; M. Macmillan; T. S. Solheim; J. A. Ross; V. E. Baracos; S. Damaraju; K. C. H. Fearon

    2014-12-01

    Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986–2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and

  1. The candidate tumor suppressor gene ECRG4 inhibits cancer cells migration and invasion in esophageal carcinoma

    Lu ShihHsin

    2010-10-01

    Full Text Available Abstract Background The esophageal cancer related gene 4 (ECRG4 was initially identified and cloned in our laboratory from human normal esophageal epithelium (GenBank accession no.AF325503. ECRG4 was a new tumor suppressor gene in esophageal squamous cell carcinoma (ESCC associated with prognosis. In this study, we investigated the novel tumor-suppressing function of ECRG4 in cancer cell migration, invasion, adhesion and cell cycle regulation in ESCC. Methods Transwell and Boyden chamber experiments were utilized to examined the effects of ECRG4 expression on ESCC cells migration, invasion and adhesion. And flow cytometric analysis was used to observe the impact of ECRG4 expression on cell cycle regulation. Finally, the expression levels of cell cycle regulating proteins p53 and p21 in human ESCC cells transfected with ECRG4 gene were evaluated by Western blotting. Results The restoration of ECRG4 expression in ESCC cells inhibited cancer cells migration and invasion (P P > 0.05. Furthermore, ECRG4 could cause cell cycle G1 phase arrest in ESCC (P Conclusion ECRG4 is a candidate tumor suppressor gene which suppressed tumor cells migration and invasion without affecting cell adhesion ability in ESCC. Furthermore, ECRG4 might cause cell cycle G1 phase block possibly through inducing the increased expression of p53 and p21 proteins in ESCC.

  2. Fine Mapping and Candidate Gene Analysis of the Leaf-Color Gene ygl-1 in Maize

    Guan, Haiying; Xu, Xiangbo; He, Chunmei; Liu, Chunxiao; Liu, Qiang; Dong, Rui; Liu, Tieshan; Wang, Liming

    2016-01-01

    A novel yellow-green leaf mutant yellow-green leaf-1 (ygl-1) was isolated in self-pollinated progenies from the cross of maize inbred lines Ye478 and Yuanwu02. The mutant spontaneously showed yellow-green character throughout the lifespan. Meanwhile, the mutant reduced contents of chlorophyll and Car, arrested chloroplast development and lowered the capacity of photosynthesis compared with the wild-type Lx7226. Genetic analysis revealed that the mutant phenotype was controlled by a recessive nuclear gene. The ygl-1 locus was initially mapped to an interval of about 0.86 Mb in bin 1.01 on the short arm of chromosome 1 using 231 yellow-green leaf individuals of an F2 segregating population from ygl-1/Lx7226. Utilizing four new polymorphic SSR markers, the ygl-1 locus was narrowed down to a region of about 48 kb using 2930 and 2247 individuals of F2 and F3 mapping populations, respectively. Among the three predicted genes annotated within this 48 kb region, GRMZM2G007441, which was predicted to encode a cpSRP43 protein, had a 1-bp nucleotide deletion in the coding region of ygl-1 resulting in a frame shift mutation. Semi-quantitative RT-PCR analysis revealed that YGL-1 was constitutively expressed in all tested tissues and its expression level was not significantly affected in the ygl-1 mutant from early to mature stages, while light intensity regulated its expression both in the ygl-1 mutant and wild type seedlings. Furthermore, the mRNA levels of some genes involved in chloroplast development were affected in the six-week old ygl-1 plants. These findings suggested that YGL-1 plays an important role in chloroplast development of maize. PMID:27100184

  3. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer.

    Sofie Claerhout

    Full Text Available BACKGROUND: Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. METHODOLOGY/PRINCIPAL FINDINGS: Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. CONCLUSIONS/SIGNIFICANCE: We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.

  4. A combination of transcriptome and methylation analyses reveals embryologically-relevant candidate genes in MRKH patients

    Riess Olaf

    2011-05-01

    Full Text Available Abstract Background The Mayer-Rokitansky-Küster-Hauser (MRKH syndrome is present in at least 1 out of 4,500 female live births and is the second most common cause for primary amenorrhea. It is characterized by vaginal and uterine aplasia in an XX individual with normal secondary characteristics. It has long been considered a sporadic anomaly, but familial clustering occurs. Several candidate genes have been studied although no single factor has yet been identified. Cases of discordant monozygotic twins suggest that the involvement of epigenetic factors is more likely. Methods Differences in gene expression and methylation patterns of uterine tissue between eight MRKH patients and eight controls were identified using whole-genome microarray analyses. Results obtained by expression and methylation arrays were confirmed by qRT-PCR and pyrosequencing. Results We delineated 293 differentially expressed and 194 differentially methylated genes of which nine overlap in both groups. These nine genes are mainly embryologically relevant for the development of the female genital tract. Conclusion Our study used, for the first time, a combined whole-genome expression and methylation approach to reveal the etiology of the MRKH syndrome. The findings suggest that either deficient estrogen receptors or the ectopic expression of certain HOXA genes might lead to abnormal development of the female reproductive tract. In utero exposure to endocrine disruptors or abnormally high maternal hormone levels might cause ectopic expression or anterior transformation of HOXA genes. It is, however, also possible that different factors influence the anti-Mullerian hormone promoter activity during embryological development causing regression of the Müllerian ducts. Thus, our data stimulate new research directions to decipher the pathogenic basis of MRKH syndrome.

  5. Identification of candidate genes for familial early-onset essential tremor.

    Liu, Xinmin; Hernandez, Nora; Kisselev, Sergey; Floratos, Aris; Sawle, Ashley; Ionita-Laza, Iuliana; Ottman, Ruth; Louis, Elan D; Clark, Lorraine N

    2016-07-01

    Essential tremor (ET) is one of the most common causes of tremor in humans. Despite its high heritability and prevalence, few susceptibility genes for ET have been identified. To identify ET genes, whole-exome sequencing was performed in 37 early-onset ET families with an autosomal-dominant inheritance pattern. We identified candidate genes for follow-up functional studies in five ET families. In two independent families, we identified variants predicted to affect function in the nitric oxide (NO) synthase 3 gene (NOS3) that cosegregated with disease. NOS3 is highly expressed in the central nervous system (including cerebellum), neurons and endothelial cells, and is one of three enzymes that converts l-arginine to the neurotransmitter NO. In one family, a heterozygous variant, c.46G>A (p.(Gly16Ser)), in NOS3, was identified in three affected ET cases and was absent in an unaffected family member; and in a second family, a heterozygous variant, c.164C>T (p.(Pro55Leu)), was identified in three affected ET cases (dizygotic twins and their mother). Both variants result in amino-acid substitutions of highly conserved amino-acid residues that are predicted to be deleterious and damaging by in silico analysis. In three independent families, variants predicted to affect function were also identified in other genes, including KCNS2 (KV9.2), HAPLN4 (BRAL2) and USP46. These genes are highly expressed in the cerebellum and Purkinje cells, and influence function of the gamma-amino butyric acid (GABA)-ergic system. This is in concordance with recent evidence that the pathophysiological process in ET involves cerebellar dysfunction and possibly cerebellar degeneration with a reduction in Purkinje cells, and a decrease in GABA-ergic tone. PMID:26508575

  6. A candidate gene for X-linked Ocular Albinism (OA1)

    Bassi, M.T.; Schiaffino, V.; Rugarli, E. [Baylor College of Medicine, Houston, TX (United States)

    1994-09-01

    Ocular Albinism of the Nettleship-Fall type 1 (OA1) is the most common form of ocular albinism. It is transmitted as an X-linked recessive trait with affected males showing severe reduction of visual acuity, nystagmus, strabismus, photophobia. Ophthalmologic examination reveals foveal hypoplasia, hypopigmentation of the retina and iris translucency. Microscopic examination of melanocytes suggests that the underlying defect in OA1 is an abnormality in melanosome formation. Recently we assembled a 350 kb cosmid contig spanning the entire critical region on Xp22.3, which measures approximately 110 kb. A minimum set of cosmids was used to identify transcribed sequences using both cDNA selection and exon amplification. Two putative exons recovered by exon amplification strategy were found to be highly conserved throughout evolution and, therefore, they were used as probes for the screening of fetal and adult retina cDNA libraries. This led to the isolation of clones spanning a full-length cDNA which measures 7.6 kb. Sequence analysis revealed that the predicted protein product shows homology with syntrophines and a Xenopus laevis apical protein. The gene covers approximately 170 kb of DNA and spans the entire critical region for OA1, being deleted in two patients with contiguous gene deletion including OA1 and in one patient with isolated OA1. Therefore, this new gene represents a very strong candidate for involvement in OA1 (an alternative, but unlikely possibility to be considered is that the true OA1 gene lies within an intron of the former). Northern analysis revealed very high level of expression in retina and melanoma. Unlike most Xp22.3 genes, this gene is conserved in the mouse. We are currently performing SSCP analysis and direct sequencing of exons on DNAs from approximately 60 unrelated patients with OA1 for mutation detection.

  7. Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

    Rasmussen, Malene B; Nielsen, Jakob V; Lourenço, Charles M;

    2014-01-01

    (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. METHODS AND RESULTS: We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural...... patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20...

  8. The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.

    Katariina Hannula-Jouppi

    2005-10-01

    Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

  9. The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia.

    2005-10-01

    Full Text Available Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples, the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

  10. Identification of Quantitative Trait Loci (QTL) and Candidate Genes for Cadmium Tolerance in Populus

    Induri, Brahma R [West Virginia University; Ellis, Danielle R [West Virginia University; Slavov, Gancho [West Virginia University; Yin, Tongming [ORNL; Muchero, Wellington [ORNL; Tuskan, Gerald A [ORNL; DiFazio, Stephen P [West Virginia University

    2012-01-01

    Knowledge of genetic variation in response of Populus to heavy metals like cadmium (Cd) is an important step in understanding the underlying mechanisms of tolerance. In this study, a pseudo-backcross pedigree of Populus trichocarpa and Populus deltoides was characterized for Cd exposure. The pedigree showed significant variation for Cd tolerance thus enabling the identification of relatively tolerant and susceptible genotypes for intensive characterization. A total of 16 QTLs at logarithm of odds (LOD) ratio > 2.5, were found to be associated with total dry weight, its components, and root volume. Four major QTLs for total dry weight were mapped to different linkage groups in control (LG III) and Cd conditions (LG XVI) and had opposite allelic effects on Cd tolerance, suggesting that these genomic regions were differentially controlled. The phenotypic variation explained by Cd QTL for all traits under study varied from 5.9% to 11.6% and averaged 8.2% across all QTL. Leaf Cd contents also showed significant variation suggesting the phytoextraction potential of Populus genotypes, though heritability of this trait was low (0.22). A whole-genome microarray study was conducted by using two genotypes with extreme responses for Cd tolerance in the above study and differentially expressed genes were identified. Candidate genes including CAD2 (CADMIUM SENSITIVE 2), HMA5 (HEAVY METAL ATPase5), ATGTST1 (Arabidopsis thaliana Glutathione S-Transferase1), ATGPX6 (Glutathione peroxidase 6), and ATMRP 14 (Arabidopsis thaliana Multidrug Resistance associated Protein 14) were identified from QTL intervals and microarray study. Functional characterization of these candidate genes could enhance phytoremediation capabilities of Populus.