Relationship between genetic polymorphisms in the DRD5 gene and paranoid schizophrenia in northern Han Chinese.

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Zhao, Y; Ding, M; Pang, H; Xu, X M; Wang, B J

2014-03-12

Dopamine (DA) has been implicated in the pathophysiol-ogy of several psychiatric disorders, including schizophrenia. Thus, genes related to the dopaminergic (DAergic) system are good candidate genes for schizophrenia. One of receptors of the DA receptor system is dopa-mine receptor 5 (DRD5). Single nucleotide polymorphisms (SNPs) in the regulatory regions of DRD5 gene may affect gene expression, influence biosynthesis of DA and underlie various neuropsychiatric disorders re-lated to DA dysfunction. The present study explored the association of SNPs within the DRD5 gene with paranoid schizophrenia in Han Chinese. A total of 176 patients with schizophrenia and 206 healthy controls were genotyped for four DRD5 SNPs (rs77434921, rs2076907, rs6283, and rs1800762). Significant group differences were observed in the allele and genotype frequencies of rs77434921 and rs1800762 and in the frequen-cies of GC haplotypes corresponding to rs77434921-rs1800762. Our find-ings suggest that common genetic variations of DRD5 are likely to con-tribute to genetic susceptibility to paranoid schizophrenia in Han Chinese. Further studies in larger samples are needed to replicate this association.

TPH2 gene polymorphisms in the regulatory region are associated with paranoid schizophrenia in Northern Han Chinese.

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Xu, X M; Ding, M; Pang, H; Wang, B J

2014-03-12

In the last years, serotonin (5-HT) has been related with the pathophysiology of several psychiatric disorders, including schizophrenia. Thus, genes related to the serotonergic (5-HTergic) system are good candidate genes for schizophrenia. The rate-limiting enzyme of 5-HT synthesis is tryptophan hydroxylase 2 (TPH2). Single nucleotide polymorphisms (SNPs) in the regulatory regions of TPH2 gene may affect gene expression and biosynthesis of 5-HT triggering to various neuropsychiatric disorders related to 5-HT dysfunction. The present study explored the association of SNPs within the TPH2 gene with paranoid schizophrenia in Han Chinese. A total of 164 patients with schizophrenia and 244 healthy controls were genotyped for six TPH2 SNPs (rs4570625, rs11178997, rs11178998, rs41317118, rs17110747, and rs41317114). Significant group differences were observed in the allele and genotype frequencies of rs4570625 and in the frequencies of GTA and TTA haplotypes corresponding to rs4570625-rs11178997-rs11178998. Our findings suggest that common genetic variations of TPH2 are likely to contribute to genetic susceptibility to paranoid schizophrenia in Han Chinese. Further studies in larger samples are needed to replicate this association.

[Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia].

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Zeng, Li-ping; Hu, Zheng-mao; Mu, Li-li; Mei, Gui-sen; Lu, Xiu-ling; Zheng, Yong-jun; Li, Pei-jian; Zhang, Ying-xue; Pan, Qian; Long, Zhi-gao; Dai, He-ping; Zhang, Zhuo-hua; Xia, Jia-hui; Zhao, Jing-ping; Xia, Kun

2011-06-01

To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR; American Psychiatric Association, 2000). All subjects signed informed consent. In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α = 0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P= 0.0367) at D1S484. The single point NPL score was 1.95(P= 0.0145) and the multi-point NPL score was 2.39 (P= 0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P= 0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive

Schizophrenia and chromosomal deletions

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Lindsay, E.A.; Baldini, A. [Baylor College of Medicine, Houston, TX (United States); Morris, M. A. [Univ. of Geneva School of Medicine, NY (United States)] [and others

1995-06-01

Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

Disease and genetic contributions toward local tissue volume disturbances in schizophrenia: a tensor-based morphometry study.

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Yang, Yaling; Nuechterlein, Keith H; Phillips, Owen R; Gutman, Boris; Kurth, Florian; Dinov, Ivo; Thompson, Paul M; Asarnow, Robert F; Toga, Arthur W; Narr, Katherine L

2012-09-01

Structural brain deficits, especially frontotemporal volume reduction and ventricular enlargement, have been repeatedly reported in patients with schizophrenia. However, it remains unclear whether brain structural deformations may be attributable to disease-related or genetic factors. In this study, the structural magnetic resonance imaging data of 48 adult-onset schizophrenia patients, 65 first-degree nonpsychotic relatives of schizophrenia patients, 27 community comparison (CC) probands, and 73 CC relatives were examined using tensor-based morphometry (TBM) to isolate global and localized differences in tissue volume across the entire brain between groups. We found brain tissue contractions most prominently in frontal and temporal regions and expansions in the putamen/pallidum, and lateral and third ventricles in schizophrenia patients when compared with unrelated CC probands. Results were similar, though less prominent when patients were compared with their nonpsychotic relatives. Structural deformations observed in unaffected patient relatives compared to age-similar CC relatives were suggestive of schizophrenia-related genetic liability and were pronounced in the putamen/pallidum and medial temporal regions. Schizophrenia and genetic liability effects for the putamen/pallidum were confirmed by regions-of-interest analysis. In conclusion, TBM findings complement reports of frontal, temporal, and ventricular dysmorphology in schizophrenia and further indicate that putamen/pallidum enlargements, originally linked mainly with medication exposure in early studies, also reflect a genetic predisposition for schizophrenia. Thus, brain deformation profiles revealed in this study may help to clarify the role of specific genetic or environmental risk factors toward altered brain morphology in schizophrenia.

Schizophrenia, vitamin D, and brain development.

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Mackay-Sim, Alan; Féron, François; Eyles, Darryl; Burne, Thomas; McGrath, John

2004-01-01

Schizophrenia research is invigorated at present by the recent discovery of several plausible candidate susceptibility genes identified from genetic linkage and gene expression studies of brains from persons with schizophrenia. It is a current challenge to reconcile this gathering evidence for specific candidate susceptibility genes with the "neurodevelopmental hypothesis," which posits that schizophrenia arises from gene-environment interactions that disrupt brain development. We make the case here that schizophrenia may result not from numerous genes of small effect, but a few genes of transcriptional regulation acting during brain development. In particular we propose that low vitamin D during brain development interacts with susceptibility genes to alter the trajectory of brain development, probably by epigenetic regulation that alters gene expression throughout adult life. Vitamin D is an attractive "environmental" candidate because it appears to explain several key epidemiological features of schizophrenia. Vitamin D is an attractive "genetic" candidate because its nuclear hormone receptor regulates gene expression and nervous system development. The polygenic quality of schizophrenia, with linkage to many genes of small effect, maybe brought together via this "vitamin D hypothesis." We also discuss the possibility of a broader set of environmental and genetic factors interacting via the nuclear hormone receptors to affect the development of the brain leading to schizophrenia.

DNA methyl transferase (DNMT gene polymorphisms could be a primary event in epigenetic susceptibility to schizophrenia.

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Koramannil Radha Saradalekshmi

Full Text Available DNA methylation has been implicated in the etiopathology of various complex disorders. DNA methyltransferases are involved in maintaining and establishing new methylation patterns. The aim of the present study was to investigate the inherent genetic variations within DNA methyltransferase genes in predisposing to susceptibility to schizophrenia. We screened for polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B and DNMT3L in 330 schizophrenia patients and 302 healthy controls for association with Schizophrenia in south Indian population. These polymorphisms were also tested for subgroup analysis with patient's gender, age of onset and family history. DNMT1 rs2114724 (genotype P = .004, allele P = 0.022 and rs2228611 (genotype P = 0.004, allele P = 0.022 were found to be significantly associated at genotypic and allelic level with Schizophrenia in South Indian population. DNMT3B rs2424932 genotype (P = 0.023 and allele (P = 0.0063 increased the risk of developing schizophrenia in males but not in females. DNMT3B rs1569686 (genotype P = 0.027, allele P = 0.033 was found to be associated with early onset of schizophrenia and also with family history and early onset (genotype P = 0.009. DNMT3L rs2070565 (genotype P = 0.007, allele P = 0.0026 confers an increased risk of developing schizophrenia at an early age in individuals with family history. In-silico prediction indicated functional relevance of these SNPs in regulating the gene. These observations might be crucial in addressing and understanding the genetic control of methylation level differences from ethnic viewpoint. Functional significance of genotype variations within the DNMTs indeed suggest that the genetic nature of methyltransferases should be considered while addressing epigenetic events mediated by methylation in Schizophrenia.

The genetic validation of heterogeneity in schizophrenia

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Moritani Makiko

2011-10-01

Full Text Available Abstract Introduction Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Methods Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Results No statistically significant deviation between cases and controls was observed in the genetic risk-index derived from all seven variants on the top-ranked polymorphisms. In fact, the average risk-index score in the schizophrenia group (6.5+/-1.57 was slightly lower than among controls (6.6+/-1.39. Conclusion The current work illustrates the difficulty in identifying universal and definitive risk-conferring polymorphisms for schizophrenia. Our employed number of samples was small, so we can not preclude the possibility that some or all of these variants are minor risk factors for schizophrenia in the Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

Gene-environment interaction and covariation in schizophrenia: the role of obstetric complications.

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Mittal, Vijay A; Ellman, Lauren M; Cannon, Tyrone D

2008-11-01

While genetic factors account for a significant proportion of liability to schizophrenia, a body of evidence attests to a significant environmental contribution. Understanding the mechanisms through which genetic and environmental factors coalesce in influencing schizophrenia is critical for elucidating the pathways underlying psychotic illness and for developing primary prevention strategies. Although obstetric complications (OCs) remain among the most well-documented environmental indicators of risk for schizophrenia, the pathogenic role they play in the etiology of schizophrenia continues to remain poorly understood. A question of major importance is do these factors result from a genetic diathesis to schizophrenia (as in gene-environment covariation), act additively or interactively with predisposing genes for the disorder in influencing disease risk, or independently cause disease onset? In this review, we evaluate 3 classes of OCs commonly related to schizophrenia including hypoxia-associated OCs, maternal infection during pregnancy, and maternal stress during pregnancy. In addition, we discuss several mechanisms by which OCs impact on genetically susceptible brain regions, increasing constitutional vulnerability to neuromaturational events and stressors later in life (ie, adolescence), which may in turn contribute to triggering psychosis.

[22q11.2DS Syndrome as a Genetic Subtype of Schizophrenia].

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Huertas-Rodríguez, Cindy Katherin; Payán-Gómez, César; Forero-Castro, Ruth Maribel

2015-01-01

The 22q11.2 deletion syndrome (22q11.2DS) is associated with the microdeletion of this chromosomal region, and represents the second most common genetic syndrome after Down's syndrome. In patients with schizophrenia, 22q11.2DS has a prevalence of 2%, and in selected groups can be increased to between 32-53%. To describe the generalities of 22q11.2DS syndrome as a genetic subtype of schizophrenia, its clinical characteristics, molecular genetic aspects, and frequency in different populations. A review was performed from 1967 to 2013 in scientific databases, compiling articles about 22q11.2DS syndrome and its association with schizophrenia. The 22q11.2 DS syndrome has a variable phenotype associated with other genetic syndromes, birth defects in many tissues and organs, and a high rate of psychiatric disorders, particularly schizophrenia. Likewise, it has been identified in clinical populations with schizophrenia selected by the presence of common syndromic characteristics. FISH, qPCR and MLPA techniques, and recently, aCGH and NGS technologies, are being used to diagnose this microdeletion. It is important in clinical practice to remember that people suffering the 22q11.2DS have a high genetic risk for developing schizophrenia, and it is considered that the simultaneous presence of this disease and 22q11.2DS represents a genetic subtype of schizophrenia. There are clear phenotypic criteria, molecular and cytogenetic methods to diagnose this group of patients, and to optimize a multidisciplinary approach in their monitoring. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

IQ and schizophrenia in a Swedish national sample: their causal relationship and the interaction of IQ with genetic risk.

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Kendler, Kenneth S; Ohlsson, Henrik; Sundquist, Jan; Sundquist, Kristina

2015-03-01

The authors sought to clarify the relationship between IQ and subsequent risk for schizophrenia. IQ was assessed at ages 18-20 in 1,204,983 Swedish males born between 1951 and 1975. Schizophrenia was assessed by hospital diagnosis through 2010. Cox proportional hazards models were used to investigate future risk for schizophrenia in individuals as a function of their IQ score, and then stratified models using pairs of relatives were used to adjust for familial cluster. Finally, regression models were used to examine the interaction between IQ and genetic liability on risk for schizophrenia. IQ had a monotonic relationship with schizophrenia risk across the IQ range, with a mean increase in risk of 3.8% per 1-point decrease in IQ; this association was stronger in the lower than the higher IQ range. Co-relative control analyses showed a similar association between IQ and schizophrenia in the general population and in cousin, half-sibling, and full-sibling pairs. A robust interaction was seen between genetic liability to schizophrenia and IQ in predicting schizophrenia risk. Genetic susceptibility for schizophrenia had a much stronger impact on risk of illness for those with low than high intelligence. The IQ-genetic liability interaction arose largely from IQ differences between close relatives. IQ assessed in late adolescence is a robust risk factor for subsequent onset of schizophrenia. This association is not the result of a declining IQ associated with insidious onset. In this large, representative sample, we found no evidence for a link between genius and schizophrenia. Co-relative control analyses showed that the association between lower IQ and schizophrenia is not the result of shared familial risk factors and may be causal. The strongest effect was seen with IQ differences within families. High intelligence substantially attenuates the impact of genetic liability on the risk for schizophrenia.

Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia

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Zhihong eJiang

2013-09-01

Full Text Available Schizophrenia etiology is thought to involve an interaction between genetic and environmental factors during postnatal brain development. However, there is a fundamental gap in our understanding of the molecular mechanisms by which environmental factors interact with genetic susceptibility to trigger symptom onset and disease progression. In this review, we summarize the most recent findings implicating oxidative stress as one mechanism by which environmental insults, especially early life social stress, impact the development of schizophrenia. Based on a review of the literature and the results of our own animal model, we suggest that environmental stressors such as social isolation render parvalbumin-positive interneurons vulnerable to oxidative stress. We previously reported that social isolation stress exacerbates many of the schizophrenia-like phenotypes seen in a conditional genetic mouse model of schizophrenia in which NMDARs are selectively ablated in half of cortical and hippocampal interneurons during early postnatal development (Belforte et al., 2010. We have since revealed that this social isolation-induced effect is caused by impairments in the antioxidant defense capacity in the parvalbumin-positive interneurons in which NMDARs are ablated. We propose that this effect is mediated by the down-regulation of PGC-1α, a master regulator of mitochondrial energy metabolism and anti-oxidant defense, following the deletion of NMDARs (Jiang et al, 2013. Other potential molecular mechanisms underlying redox dysfunction upon gene and environmental interaction will be discussed, with a focus on the unique properties of parvalbumin-positive interneurons.

Tumor necrosis factor-α and -β genetic polymorphisms as a risk factor in Saudi patients with schizophrenia

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Kadasah S

2017-04-01

Full Text Available Saeed Kadasah,1 Misbahul Arfin,2 Sadaf Rizvi,2 Mohammed Al-Asmari,2 Abdulrahman Al-Asmari2 1Department of Psychiatry, 2Division of Molecular Biology & Genetics, Scientific Research Center, Prince Sultan Military Medical City, Riyadh, Saudi Arabia Background: Schizophrenia is one of the most common devastating psychiatric disorders that negatively affects the quality of life and psychosocial functions. Its etiology involves the interplay of complex polygenic influences and environmental risk factors. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia. Objective: The aim of this study was to investigate the association of proinflammatory cytokine genes, tumor necrosis factor (TNF-α (-308G/A and TNF-β (+252A/G polymorphisms with schizophrenia susceptibility. Subjects and methods: TNF-α and TNF-β genes were amplified using amplification refractory mutation system primers in 180 schizophrenia patients and 200 healthy matched controls recruited from the Psychiatry Clinic of Prince Sultan Military Medical City, Riyadh. The frequencies of alleles and genotypes of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms in patients were compared with those in controls. Results: The frequencies of TNF-α (-308 allele A and genotype GA were significantly higher, while those of allele G and genotype GG were lower in schizophrenia patients as compared to controls, indicating that genotype GA and allele A of TNF-α (-308G/A may increase susceptibility to schizophrenia, while genotype GG and allele G may reduce it. On the other hand, the distribution of alleles and genotypes of TNF-β (+252A/G polymorphism does not differ significantly in patients from controls; however, the frequency of genotype GG of TNF-β (+252A/G was significantly higher in male patients than in female patients. The distribution of TNF-α (-308G/A and TNF-β (+252A/G polymorphisms was almost similar in schizophrenia patients with

Disturbed functional connectivity of cortical activation during semantic discrimination in patients with schizophrenia and subjects at genetic high-risk.

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Li, Xiaobo; Branch, Craig A; Nierenberg, Jay; Delisi, Lynn E

2010-03-01

Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca's area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca's area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca's area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.

The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia.

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Su, Yousong; Ding, Wenhua; Xing, Mengjuan; Qi, Dake; Li, Zezhi; Cui, Donghong

2017-08-01

Although previous studies showed the reduced risk of cancer in patients with schizophrenia, whether patients with schizophrenia possess genetic factors that also contribute to tumor suppressor is still unknown. In the present study, based on our previous microarray data, we focused on the tumor suppressor genes TXNIP and AF1q, which differentially expressed in patients with schizophrenia. A total of 413 patients and 578 healthy controls were recruited. We found no significant differences in genotype, allele, or haplotype frequencies at the selected five single nucleotide polymorphisms (SNPs) (rs2236566 and rs7211 in TXNIP gene; rs10749659, rs2140709, and rs3738481 in AF1q gene) between patients with schizophrenia and controls. However, we found the association between the interaction of TXNIP and AF1q with schizophrenia by using the MDR method followed by traditional statistical analysis. The best gene-gene interaction model identified was a three-locus model TXNIP (rs2236566, rs7211)-AF1q (rs2140709). After traditional statistical analysis, we found the high-risk genotype combination was rs2236566 (GG)-rs7211(CC)-rs2140709(CC) (OR = 1.35 [1.03-1.76]). The low-risk genotype combination was rs2236566 (GT)-rs7211(CC)-rs2140709(CC) (OR = 0.67 [0.49-0.91]). Our finding suggested statistically significant role of interaction of TXNIP and AF1q polymorphisms (TXNIP-rs2236566, TXNIP-rs7211, and AF1q-rs2769605) in schizophrenia susceptibility.

The genetic validation of heterogeneity in schizophrenia.

Science.gov (United States)

Tsutsumi, Atsushi; Glatt, Stephen J; Kanazawa, Tetsufumi; Kawashige, Seiya; Uenishi, Hiroyuki; Hokyo, Akira; Kaneko, Takao; Moritani, Makiko; Kikuyama, Hiroki; Koh, Jun; Matsumura, Hitoshi; Yoneda, Hiroshi

2011-10-07

Schizophrenia is a heritable disorder, however clear genetic architecture has not been detected. To overcome this state of uncertainty, the SZGene database has been established by including all published case-control genetic association studies appearing in peer-reviewed journals. In the current study, we aimed to determine if genetic variants strongly suggested by SZGene are associated with risk of schizophrenia in our case-control samples of Japanese ancestry. In addition, by employing the additive model for aggregating the effect of seven variants, we aimed to verify the genetic heterogeneity of schizophrenia diagnosed by an operative diagnostic manual, the DSM-IV. Each positively suggested genetic polymorphism was ranked according to its p-value, then the seven top-ranked variants (p Japanese population. It is also important to aggregate the updated positive variants in the SZGene database when the replication work is conducted.

Paradox of schizophrenia genetics: is a paradigm shift occurring?

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Doi Nagafumi

2012-05-01

Full Text Available Abstract Background Genetic research of schizophrenia (SCZ based on the nuclear genome model (NGM has been one of the most active areas in psychiatry for the past two decades. Although this effort is ongoing, the current situation of the molecular genetics of SCZ seems disappointing or rather perplexing. Furthermore, a prominent discrepancy between persistence of the disease at a relatively high prevalence and a low reproductive fitness of patients creates a paradox. Heterozygote advantage works to sustain the frequency of a putative susceptibility gene in the mitochondrial genome model (MGM but not in the NGM. Methods We deduced a criterion that every nuclear susceptibility gene for SCZ should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. SCZ-associated variants listed in the top 45 in the SZGene Database (the version of the 23rd December, 2011 were selected, and the distribution of the genes that could meet or do not meet the criterion was surveyed. Results 19 SCZ-associated variants that do not meet the criterion are located outside the regions where the SCZ-associated variants that could meet the criterion are located. Since a SCZ-associated variant that does not meet the criterion cannot be a susceptibility gene, but instead must be a protective gene, it should be linked to a susceptibility gene in the NGM, which is contrary to these results. On the other hand, every protective gene on any chromosome can be associated with SCZ in the MGM. Based on the MGM we propose a new hypothesis that assumes brain-specific antioxidant defenses in which trans-synaptic activations of dopamine- and N-methyl-d-aspartate-receptors are involved. Most of the ten predictions of this hypothesis seem to accord with the major epidemiological facts and the results of association studies to date. Conclusion The central paradox of SCZ genetics and the results of association studies to date argue against

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

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Mössner, R; Schumacher, A; Wagner, M; Lennertz, L; Steinbrecher, A; Quednow, Boris B; Rujescu, D; Rietschel, M; Maier, W

2012-01-01

Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive sympto...

Genetic architecture for susceptibility to gout in the KARE cohort study.

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Shin, Jimin; Kim, Younyoung; Kong, Minyoung; Lee, Chaeyoung

2012-06-01

This study aimed to identify functional associations of cis-regulatory regions with gout susceptibility using data resulted from a genome-wide association study (GWAS), and to show a genetic architecture for gout with interaction effects among genes within each of the identified functions. The GWAS was conducted with 8314 control subjects and 520 patients with gout in the Korea Association REsource cohort. However, genetic associations with any individual nucleotide variants were not discovered by Bonferroni multiple testing in the GWAS (P>1.42 × 10(-7)). Genomic regions enrichment analysis was employed to identify functional associations of cis-regulatory regions. This analysis revealed several biological processes associated with gout susceptibility, and they were quite different from those with serum uric acid level. Epistasis for susceptibility to gout was estimated using entropy decomposition with selected genes within each biological process identified by the genomic regions enrichment analysis. Some epistases among nucleotide sequence variants for gout susceptibility were found to be larger than their individual effects. This study provided the first evidence that genetic factors for gout susceptibility greatly differed from those for serum uric acid level, which may suggest that research endeavors for identifying genetic factors for gout susceptibility should not be heavily dependent on pathogenesis of uric acid. Interaction effects between genes should be examined to explain a large portion of phenotypic variability for gout susceptibility.

Genetic and family counselling for schizophrenia: Where do we ...

African Journals Online (AJOL)

Background: Recent genetic findings have led to profound changes in genetic and family counselling for schizophrenia patients and their families. Objectives: The article gives an overview of the present knowledge regarding the genetic and family counselling for schizophrenia. Method: Literature searches were performed ...

Genetic liability, prenatal health, stress and family environment: risk factors in the Harvard Adolescent Family High Risk for schizophrenia study.

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Walder, Deborah J; Faraone, Stephen V; Glatt, Stephen J; Tsuang, Ming T; Seidman, Larry J

2014-08-01

The familial ("genetic") high-risk (FHR) paradigm enables assessment of individuals at risk for schizophrenia based on a positive family history of schizophrenia in first-degree, biological relatives. This strategy presumes genetic transmission of abnormal traits given high heritability of the illness. It is plausible, however, that adverse environmental factors are also transmitted in these families. Few studies have evaluated both biological and environmental factors within a FHR study of adolescents. We conceptualize four precursors to psychosis pathogenesis: two biological (genetic predisposition, prenatal health issues (PHIs)) and two environmental (family environment, stressful life events (SLEs)). Participants assessed between 1998 and 2007 (ages 13-25) included 40 (20F/20M) adolescents at FHR for schizophrenia (FHRs) and 55 (31F/24M) community controls. 'Genetic load' indexed number of affected family members relative to pedigree size. PHI was significantly greater among FHRs, and family cohesion and expressiveness were less (and family conflict was higher) among FHRs; however, groups did not significantly differ in SLE indices. Among FHRs, genetic liability was significantly associated with PHI and family expressiveness. Prenatal and family environmental disruptions are elevated in families with a first-degree relative with schizophrenia. Findings support our proposed 'polygenic neurodevelopmental diathesis-stress model' whereby psychosis susceptibility (and resilience) involves the independent and synergistic confluence of (temporally-sensitive) biological and environmental factors across development. Recognition of biological and social environmental influences across critical developmental periods points to key issues relevant for enhanced identification of psychosis susceptibility, facilitation of more precise models of illness risk, and development of novel prevention strategies. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetic influences on schizophrenia and subcortical brain volumes

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Franke, Barbara; Stein, Jason L; Ripke, Stephan

2016-01-01

and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between...... genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk...

Polymorphisms of XRCC4 are involved in reduced colorectal cancer risk in Chinese schizophrenia patients

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Li Tao

2010-10-01

Full Text Available Abstract Background Genetic factors related to the regulation of apoptosis in schizophrenia patients may be involved in a reduced vulnerability to cancer. XRCC4 is one of the potential candidate genes associated with schizophrenia which might induce colorectal cancer resistance. Methods To examine the genetic association between colorectal cancer and schizophrenia, we analyzed five SNPs (rs6452526, rs2662238, rs963248, rs35268, rs2386275 covering ~205.7 kb in the region of XRCC4. Results We observed that two of the five genetic polymorphisms showed statistically significant differences between 312 colorectal cancer subjects without schizophrenia and 270 schizophrenia subjects (rs6452536, p = 0.004, OR 0.61, 95% CI 0.44-0.86; rs35268, p = 0.028, OR 1.54, 95% CI 1.05-2.26. Moreover, the haplotype which combined all five markers was the most significant, giving a global p = 0.0005. Conclusions Our data firstly indicate that XRCC4 may be a potential protective gene towards schizophrenia, conferring reduced susceptibility to colorectal cancer in the Han Chinese population.

Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population.

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Wen, Zujia; Chen, Jianhua; Khan, Raja Amjad Waheed; Song, Zhijian; Wang, Meng; Li, Zhiqiang; Shen, Jiawei; Li, Wenjin; Shi, Yongyong

2016-04-01

Schizophrenia, major depressive disorder, and bipolar disorder are three major psychiatric disorders affecting around 0.66%, 3.3%, and 1.5% of the Han Chinese population respectively. Several genetic linkage analyses and genome wide association studies identified NRG1 as a susceptibility gene of schizophrenia, which was validated by its role in neurodevelopment, glutamate, and other neurotransmitter receptor expression regulation. To further investigate whether NRG1 is a shared risk gene for major depressive disorder, bipolar disorder as well as schizophrenia, we performed an association study among 1,248 schizophrenia cases, 1,056 major depression cases, 1,344 bipolar disorder cases, and 1,248 controls. Totally 15 tag SNPs were genotyped and analyzed, and no population stratification was found in our sample set. Among the sites, rs4236710 (corrected Pgenotye  = 0.015) and rs4512342 (Pallele  = 0.03, Pgenotye  = 0.045 after correction) were associated with schizophrenia, and rs2919375 (corrected Pgenotye  = 0.004) was associated with major depressive disorder. The haplotype rs4512342-rs6982890 showed association with schizophrenia (P = 0.03 for haplotype "TC" after correction), and haplotype rs4531002-rs11989919 proved to be a shared risk factor for both major depressive disorder ("CC": corrected P = 0.009) and bipolar disorder ("CT": corrected P = 0.003). Our results confirmed that NRG1 was a shared common susceptibility gene for major mental disorders in Han Chinese population. © 2016 Wiley Periodicals, Inc.

Genetic Basis of Positive and Negative Symptom Domains in Schizophrenia.

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Xavier, Rose Mary; Vorderstrasse, Allison

2017-10-01

Schizophrenia is a highly heritable disorder, the genetic etiology of which has been well established. Yet despite significant advances in genetics research, the pathophysiological mechanisms of this disorder largely remain unknown. This gap has been attributed to the complexity of the polygenic disorder, which has a heterogeneous clinical profile. Examining the genetic basis of schizophrenia subphenotypes, such as those based on particular symptoms, is thus a useful strategy for decoding the underlying mechanisms. This review of literature examines the recent advances (from 2011) in genetic exploration of positive and negative symptoms in schizophrenia. We searched electronic databases PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature using key words schizophrenia, symptoms, positive symptoms, negative symptoms, cognition, genetics, genes, genetic predisposition, and genotype in various combinations. We identified 115 articles, which are included in the review. Evidence from these studies, most of which are genetic association studies, identifies shared and unique gene associations for the symptom domains. Genes associated with neurotransmitter systems and neuronal development/maintenance primarily constitute the shared associations. Needed are studies that examine the genetic basis of specific symptoms within the broader domains in addition to functional mechanisms. Such investigations are critical to developing precision treatment and care for individuals afflicted with schizophrenia.

Working memory in schizophrenia: behavioral and neural evidence for reduced susceptibility to item-specific proactive interference.

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Kaller, Christoph P; Loosli, Sandra V; Rahm, Benjamin; Gössel, Astrid; Schieting, Stephan; Hornig, Tobias; Hennig, Jürgen; Tebartz van Elst, Ludger; Weiller, Cornelius; Katzev, Michael

2014-09-15

Susceptibility to item-specific proactive interference (PI) contributes to interindividual differences in working memory (WM) capacity and complex cognition relying on WM. Although WM deficits are a well-recognized impairment in schizophrenia, the underlying pathophysiological effects on specific WM control functions, such as the ability to resist item-specific PI, remain unknown. Moreover, opposing hypotheses on increased versus reduced PI susceptibility in schizophrenia are both justifiable by the extant literature. To provide first insights into the behavioral and neural correlates of PI-related WM control in schizophrenia, a functional magnetic resonance imaging experiment was conducted in a sample of 20 patients and 20 well-matched control subjects. Demands on item-specific PI were experimentally manipulated in a recent-probes task (three runs, 64 trials each) requiring subjects to encode and maintain a set of four target items per trial. Compared with healthy control subjects, schizophrenia patients showed a significantly reduced PI susceptibility in both accuracy and latency measures. Notably, reduced PI susceptibility in schizophrenia was not associated with overall WM impairments and thus constituted an independent phenomenon. In addition, PI-related activations in inferior frontal gyrus and anterior insula, typically assumed to support PI resistance, were reduced in schizophrenia, thus ruling out increased neural efforts as a potential cause of the patients' reduced PI susceptibility. The present study provides first evidence for a diminished vulnerability of schizophrenia patients to item-specific PI, which is presumably a consequence of the patients' more efficient clearing of previously relevant WM traces and the accordingly reduced likelihood for item-specific PI to occur. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Association of the 3′ Region of COMT with Schizophrenia in Taiwan

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Yi-Ling Chien

2009-04-01

Conclusion: The SNP rs165599, which has been mapped to the 3′-UTR region of the COMT gene, was significantly associated with schizophrenia in our family study, and possibly associated with the age of onset, delusion/hallucination symptom dimension, and CPT performance. Therefore, COMT may contribute to the genetic risk for schizophrenia not through the Val108/158 Met polymorphism, but through other variants that are situated 3′ to this region, in the Taiwanese population. Nevertheless, the true associated functional variants in our subjects remain to be elucidated.

Comparative linkage meta-analysis reveals regionally-distinct, disparate genetic architectures: application to bipolar disorder and schizophrenia.

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Brady Tang

2011-04-01

Full Text Available New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for "missing heritability." However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS, alternative approaches robust to detection of low-frequency (1-5% MAF and rare (<1% variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods--GSMA and MSP--applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA may be used to optimize low-frequency and rare variant discovery in the modern genomic era.

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

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Gottesman Irving I

2005-02-01

Full Text Available Abstract Background Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. Discussion A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular

[Risk factors of schizophrenia].

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Suvisaari, Jaana

2010-01-01

Schizophrenia is a multifactorial, neurodevelopmental disorder caused by a combination of genetic and environmental risk factors. Disturbances of brain development begin prenatally, while different environmental insults further affect postnatal brain maturation during childhood and adolescence. Genome-wide association studies (GWAS) have succeeded in identifying hundreds of new risk variants for common, multifactorial diseases. In schizophrenia research, GWAS have found several rare copy number variants that considerably increase the risk of schizophrenia, and have shown an association between schizophrenia and the major histocompatibility complex. Research on environmental risk factors in recent years has provided new information particularly on risk factors related to pregnancy and childhood rearing environment. Gene-environment interactions have become a central research topic. There is evidence that genetically susceptible children are more vulnerable to the effects of unstable childhood rearing environment and other environmental risk factors.

Identification of genetic loci shared between schizophrenia and the Big Five personality traits.

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Smeland, Olav B; Wang, Yunpeng; Lo, Min-Tzu; Li, Wen; Frei, Oleksandr; Witoelar, Aree; Tesli, Martin; Hinds, David A; Tung, Joyce Y; Djurovic, Srdjan; Chen, Chi-Hua; Dale, Anders M; Andreassen, Ole A

2017-05-22

Schizophrenia is associated with differences in personality traits, and recent studies suggest that personality traits and schizophrenia share a genetic basis. Here we aimed to identify specific genetic loci shared between schizophrenia and the Big Five personality traits using a Bayesian statistical framework. Using summary statistics from genome-wide association studies (GWAS) on personality traits in the 23andMe cohort (n = 59,225) and schizophrenia in the Psychiatric Genomics Consortium cohort (n = 82,315), we evaluated overlap in common genetic variants. The Big Five personality traits neuroticism, extraversion, openness, agreeableness and conscientiousness were measured using a web implementation of the Big Five Inventory. Applying the conditional false discovery rate approach, we increased discovery of genetic loci and identified two loci shared between neuroticism and schizophrenia and six loci shared between openness and schizophrenia. The study provides new insights into the relationship between personality traits and schizophrenia by highlighting genetic loci involved in their common genetic etiology.

Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia

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Takao Keizo

2008-10-01

Full Text Available Abstract Background Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1 gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy mouse, which has a deletion in the Dtnbp1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study. Results In a rotarod test, sdy mice did not exhibit motor learning whilst the wild type mice did. In a Barnes circular maze test both sdy mice and wild type mice learned to selectively locate the escape hole during the course of the training period and in the probe trial conducted 24 hours after last training. However, sdy mice did not locate the correct hole in the retention probe tests 7 days after the last training trial, whereas wild type mice did, indicating impaired long-term memory retention. A T-maze forced alternation task, a task of working memory, revealed no effect of training in sdy mice despite the obvious effect of training in wild type mice, suggesting a working memory deficit. Conclusion Sdy mouse showed impaired long-term memory retention and working memory. Since genetic variation in DTNBP1 is associated with both schizophrenia and memory function, and memory function is compromised in patients with schizophrenia, the sdy mouse may represent a useful animal model to investigate the mechanisms of memory dysfunction in the disorder.

Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure.

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Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

2016-09-01

Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying these genetic markers using a multivariate twin modeling approach can provide novel leads for (genetic) pathways of schizophrenia development. In a sample of 70 twins discordant for schizophrenia and 130 healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on human brain structure (cortical thickness, cortical surface and global white matter fractional anisotropy [FA]), intellectual ability and schizophrenia liability. In total, up to 28.1% of the genetic variance (22.8% of total variance) in schizophrenia liability was shared with intelligence quotient (IQ), global-FA, cortical thickness, and cortical surface. The strongest contributor was IQ, sharing on average 16.4% of the genetic variance in schizophrenia liability, followed by cortical thickness (6.3%), global-FA (4.7%) and cortical surface (0.5%). Furthermore, we found that up to 57.4% of the variation due to environmental factors (4.6% of total variance) in schizophrenia was shared with IQ (34.2%) and cortical surface (13.4%). Intellectual ability, FA and cortical thickness show significant and independent shared genetic variance with schizophrenia liability. This suggests that measuring brain-imaging phenotypes helps explain genetic variance in schizophrenia liability that is not captured by variation in IQ. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

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McLaughlin, Russell L; Schijven, Dick; van Rheenen, Wouter

2017-01-01

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome...

Association between variations in the disrupted in schizophrenia 1 gene and schizophrenia: A meta-analysis.

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Xu, Yiliang; Ren, Jun; Ye, Haihong

2018-04-20

Schizophrenia is a severe psychiatric disorder. Genetic and functional studies have strongly implicated the disrupted in schizophrenia 1 gene (DISC1) as a candidate susceptibility gene for schizophrenia. Moreover, recent association studies have indicated that several DISC1 single nucleotide polymorphisms (SNPs) are associated with schizophrenia. However, the association is hardly replicate in different ethnic group. Here, we performed a meta-analysis of the association between DISC1 SNPs and schizophrenia in which the samples were divided into subgroups according to ethnicity. Both rs3738401 and rs821616 showed not significantly association with schizophrenia in the Caucasian, Asian, Japanese or Han Chinese populations. Copyright © 2018 Elsevier B.V. All rights reserved.

Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

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Cardno, Alastair G.

2014-01-01

There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant. PMID:24567502

Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility.

LENUS (Irish Health Repository)

O'Dushlaine, C

2011-03-01

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant (P<0.05) to nonsignificant SNPs in a given pathway to identify the \\'enrichment\\' for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium (n=6909)) and validation (Genetic Association Information Network (n=2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant (P=0.03-0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium (n=4847)) (P=0.01). At a gene level, CAM genes associated in all three samples (NRXN1 and CNTNAP2), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Gender differences in susceptibility to schizophrenia: Potential implication of neurosteroids.

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Huang, Yu-Chi; Hung, Chi-Fa; Lin, Pao-Yen; Lee, Yu; Wu, Chih-Ching; Hsu, Su-Ting; Chen, Chien-Chih; Chong, Mian-Yoon; Lin, Chieh-Hsin; Wang, Liang-Jen

2017-10-01

Past research has indicated gender differences in the clinical characteristics and course of schizophrenia. In this study, we investigated whether gender differences in the manifestation of schizophrenia are correlated with neurosteroids, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and pregnenolone. We further explored the potential relationship between the aforementioned neurosteroids and psychopathology. We recruited 65 schizophrenic patients (36 males and 29 females) and 103 healthy control subjects (47 males and 56 females) and obtained blood samples from the subjects in the morning while in a fasting state to determine the serum levels of DHEA, DHEA-S, and pregnenolone. The psychopathology and mood symptoms of patients with schizophrenia were evaluated using the Positive and Negative Syndrome Scale (PANSS) and 17-item Hamilton Depression Rating Scale, respectively. Compared to the male control subjects, male patients with schizophrenia had significantly lower serum levels of DHEA and pregnenolone. In males with schizophrenia, the serum levels of DHEA and DHEA-S were associated with the age of onset and the duration of illness, while pregnenolone levels were associated with general symptoms of the PANSS. However, none of the neurosteroid levels were different between the female patients with schizophrenia and the female controls, and no significant correlation between neurosteroid levels and psychopathology evaluations was found among the schizophrenic females. Neurosteroids, including DHEA, DHEA-S, and pregnenolone, are involved in the pathophysiology of schizophrenia in male patients, but not in female ones. Therefore, our findings suggest that neurosteroids may be associated with gender differences in susceptibility to schizophrenia. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

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Blokland, Gabriëlla A M; Del Re, Elisabetta C; Mesholam-Gately, Raquelle I; Jovicich, Jorge; Trampush, Joey W; Keshavan, Matcheri S; DeLisi, Lynn E; Walters, James T R; Turner, Jessica A; Malhotra, Anil K; Lencz, Todd; Shenton, Martha E; Voineskos, Aristotle N; Rujescu, Dan; Giegling, Ina; Kahn, René S; Roffman, Joshua L; Holt, Daphne J; Ehrlich, Stefan; Kikinis, Zora; Dazzan, Paola; Murray, Robin M; Di Forti, Marta; Lee, Jimmy; Sim, Kang; Lam, Max; Wolthusen, Rick P F; de Zwarte, Sonja M C; Walton, Esther; Cosgrove, Donna; Kelly, Sinead; Maleki, Nasim; Osiecki, Lisa; Picchioni, Marco M; Bramon, Elvira; Russo, Manuela; David, Anthony S; Mondelli, Valeria; Reinders, Antje A T S; Falcone, M Aurora; Hartmann, Annette M; Konte, Bettina; Morris, Derek W; Gill, Michael; Corvin, Aiden P; Cahn, Wiepke; Ho, New Fei; Liu, Jian Jun; Keefe, Richard S E; Gollub, Randy L; Manoach, Dara S; Calhoun, Vince D; Schulz, S Charles; Sponheim, Scott R; Goff, Donald C; Buka, Stephen L; Cherkerzian, Sara; Thermenos, Heidi W; Kubicki, Marek; Nestor, Paul G; Dickie, Erin W; Vassos, Evangelos; Ciufolini, Simone; Reis Marques, Tiago; Crossley, Nicolas A; Purcell, Shaun M; Smoller, Jordan W; van Haren, Neeltje E M; Toulopoulou, Timothea; Donohoe, Gary; Goldstein, Jill M; Seidman, Larry J; McCarley, Robert W; Petryshen, Tracey L

2018-05-01

Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both pneuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic risk for schizophrenia, obstetric complications, and adolescent school outcome: evidence for gene-environment interaction.

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Forsyth, Jennifer K; Ellman, Lauren M; Tanskanen, Antti; Mustonen, Ulla; Huttunen, Matti O; Suvisaari, Jaana; Cannon, Tyrone D

2013-09-01

Low birth weight (LBW) and hypoxia are among the environmental factors most reliably associated with schizophrenia; however, the nature of this relationship is unclear and both gene-environment interaction and gene-environment covariation models have been proposed as explanations. High-risk (HR) designs that explore whether obstetric complications differentially predict outcomes in offspring at low risk (LR) vs HR for schizophrenia, while accounting for differences in rates of maternal risk factors, may shed light on this question. This study used prospectively obtained data to examine relationships between LBW and hypoxia on school outcome at age 15-16 years in a Finnish sample of 1070 offspring at LR for schizophrenia and 373 offspring at HR for schizophrenia, based on parental psychiatric history. Controlling for offspring sex, maternal smoking, social support, parity, age, and number of prenatal care visits, HR offspring performed worse than LR offspring across academic, nonacademic, and physical education domains. LBW predicted poorer academic and physical education performance in HR offspring, but not in LR offspring, and this association was similar for offspring of fathers vs mothers with schizophrenia. Hypoxia predicted poorer physical education score across risk groups. Rates of LBW and hypoxia were similar for LR and HR offspring and for offspring of fathers vs mothers with schizophrenia. Results support the hypothesis that genetic susceptibility to schizophrenia confers augmented vulnerability of the developing brain to the effects of obstetric complications, possibly via epigenetic mechanisms.

Neurocognitive functioning in parents of schizophrenia patients: Attentional and executive performance vary with genetic loading.

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Schulze-Rauschenbach, Svenja; Lennertz, Leonhard; Ruhrmann, Stephan; Petrovsky, Nadine; Ettinger, Ulrich; Pukrop, Ralf; Dreher, Jan; Klosterkötter, Joachim; Maier, Wolfgang; Wagner, Michael

2015-12-30

Neuropsychological deficits are candidate endophenotypes of schizophrenia which can assist to explain the neurocognitive impact of genetic risk variants. The identification of endophenotypes is often based on the familiality of these phenotypes. Several studies demonstrate neuropsychological deficits in unaffected biological relatives of schizophrenia patients without differentiating between genetic and non-genetic factors underlying these deficits. We assessed N=129 unaffected biological parents of schizophrenia patients, N=28 schizophrenia patients (paranoid subtype), and N=143 controls without a family history of schizophrenia with an extensive neuropsychological test battery. Direct comparison of N=22 parents with an ancestral history of schizophrenia (more likely carriers, MLC) and N=17 of their spouses without such a history (less likely carriers, LLC) allowed the separation of genetic and non-genetic aspects in cognition. Overall, parents showed significant deficits in neuropsychological tasks from all cognitive domains with medium effect sizes. Direct comparisons of MLC- and LLC-parents showed that attentional and executive tasks were most strongly affected by genetic loading. To conclude, unaffected parents of schizophrenia patients showed modest yet significant impairments in attention, memory, and executive functioning. In particular, attentional and executive impairments varied most strongly with genetic loading for schizophrenia, prioritising these dysfunctions for genotype-endophenotype analyses. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

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Zheng Lin

Full Text Available The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2 is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445 and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445 and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605, in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605 may be involved in the susceptibility to paranoid

The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

Science.gov (United States)

Lin, Zheng; Su, Yousong; Zhang, Chengfang; Xing, Mengjuan; Ding, Wenhua; Liao, Liwei; Guan, Yangtai; Li, Zezhi; Cui, Donghong

2013-01-01

The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

A recombination hotspot in a schizophrenia-associated region of GABRB2.

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Siu-Kin Ng

Full Text Available BACKGROUND: Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the beta(2 subunit of GABA(A receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs and containing schizophrenia-associated SNPs and haplotypes. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, the possible occurrence of recombination in this 'S1-S29' segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (H(d over mutation rate (theta, was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia. CONCLUSIONS/SIGNIFICANCE: The co-occurrence of hotspot recombination and positive selection in the S1-S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and

A Danish Twin Study of Schizophrenia Liability: Investigation from Interviewed Twins for Genetic Links to Affective Psychoses and for Cross-Cohort Comparisons.

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Kläning, Ulla; Trumbetta, Susan L; Gottesman, Irving I; Skytthe, Axel; Kyvik, Kirsten O; Bertelsen, Aksel

2016-03-01

We studied schizophrenia liability in a Danish population-based sample of 44 twin pairs (13 MZ, 31 DZ, SS plus OS) in order to replicate previous twin study findings using contemporary diagnostic criteria, to examine genetic liability shared between schizophrenia and other disorders, and to explore whether variance in schizophrenia liability attributable to environmental factors may have decreased with successive cohorts exposed to improvements in public health. ICD-10 diagnoses were determined by clinical interview. Although the best-fitting, most parsimonious biometric model of schizophrenia liability specified variance attributable to additive genetic and non-shared environmental factors, this model did not differ significantly from a model that also included non-additive genetic factors, consistent with recent interview-based twin studies. Schizophrenia showed strong genetic links to other psychotic disorders but much less so for the broader category of psychiatric disorders in general. We also observed a marginally significant decline in schizophrenia variance attributable to environmental factors over successive Western European cohorts, consistent perhaps with improvements in diagnosis and in prenatal and perinatal care and with a secular decline in the prevalence of schizophrenia in that region.

Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility?

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Sunil Vasu Kalmady

Full Text Available Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6 in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls.We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla - MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms.Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women.Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic

[Correlation between genetic polymorphisms of -855 G/C and -1140 G/A in GRIN1 gene and paranoid schizophrenia].

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Li, Zhong-Jie; Ding, Mei; Pang, Hao; Sun, Xue-Fei; Xing, Jia-Xin; Xuan, Jin-Feng; Wang, Bao-Jie

2013-04-01

To investigate the single nucleotide polymorphisms (SNP) of -855 G/C and -1140 G/A in promoter regions of GRIN1 gene and find their genetic correlation to paranoid schizophrenia as well as their applicable values in forensic medicine. The genetic polymorphisms of -855 G/C and -1140 G/A at the 5' end of GRIN1 gene were detected by PCR restriction fragment length polymorphism and PAGE in 183 healthy unrelated individuals of northern Chinese Han population and 172 patients of paranoid schizophrenia, respectively. The chi2 test was used to identify Hardy-Weinberg equilibrium of the genotype distribution. The differences of genotypes and allelic frequency distributions were compared between the two groups. Distributions of the genotypic frequencies satisfied Hardy-Weinberg equilibrium in both groups. The difference of genotypes was statistically significant between female patient group and female control group in -855 G/C distribution (P paranoid schizophrenia. The genetic factor of schizophrenia is involved in gender tendency. And it could be useful in forensic identification of schizophrenia.

Animal model for schizophrenia that reflects gene-environment interactions.

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Nagai, Taku; Ibi, Daisuke; Yamada, Kiyofumi

2011-01-01

Schizophrenia is a devastating psychiatric disorder that impairs mental and social functioning and affects approximately 1% of the population worldwide. Genetic susceptibility factors for schizophrenia have recently been reported, some of which are known to play a role in neurodevelopment; these include neuregulin-1, dysbindin, and disrupted-in-schizophrenia 1 (DISC1). Moreover, epidemiologic studies suggest that environmental insults, such as prenatal infection and perinatal complication, are involved in the development of schizophrenia. The possible interaction between environment and genetic susceptibility factors, especially during neurodevelopment, is proposed as a promising disease etiology of schizophrenia. Polyriboinosinic-polyribocytidilic acid (polyI : C) is a synthetic analogue of double-stranded RNA that leads to the pronounced but time-limited production of pro-inflammatory cytokines. Maternal immune activation by polyI : C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive, and pharmacological abnormalities in adult offspring. Recently, we have reported that neonatal injection of polyI : C in mice results in schizophrenia-like behavioral alterations in adulthood. In this review, we show how gene-environment interactions during neurodevelopment result in phenotypic changes in adulthood by injecting polyI : C into transgenic mice that express a dominant-negative form of human DISC1 (DN-DISC1). Our findings suggest that polyI : C-treated DN-DISC1 mice are a well-validated animal model for schizophrenia that reflects gene-environment interactions.

Human growth hormone-related latrogenic Creutzfeldt-Jakob disease: Search for a genetic susceptibility by analysis of the PRNP coding region

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Jaegly, A.; Boussin, F.; Deslys, J.P. [CEA/CRSSA/DSV/DPTE, Fontenay-aux-Roses (France)] [and others

1995-05-20

The human PRNP gene encoding PrP is located on chromosome 20 and consists of two exons and a single intron. The open reading frame is entirely fitted into the second exon. Genetic studies indicate that all of the familial and several sporadic forms of TSSEs are associated with mutations in the PRNP 759-bp coding region. Moreover, homozygosity at codon 129, a locus harboring a polymorphism among the general population, was proposed as a genetic susceptibility marker for both sporadic and iatrogenic CJD. To assess whether additional genetic predisposition markers exist in the PRNP gene, the authors sequenced the PRNP coding region of 17 of the 32 French patients who developed a hGH-related CJD.

Genome-wide association study of schizophrenia in Japanese population.

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Kazuo Yamada

Full Text Available Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions. The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila-like 2] gene located on 9p21.3 (p = 0.00087. In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026. The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.

Genetic counseling for schizophrenia: a review of referrals to a provincial medical genetics program from 1968–2007

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Hunter, MJ; Hippman, Catriona; Honer, William G; Austin, Jehannine C.

2014-01-01

Purpose Recent studies have shown that individuals with schizophrenia and their family members are interested in genetic counseling, but few have received this service. We conducted an exploratory, retrospective study to describe (a) the population of individuals who were referred to the provincial program for genetic counseling for a primary indication of schizophrenia, and (b) trends in number of referrals between 1968 and 2007. Methods Referrals for a primary indication of schizophrenia were identified through the provincial program database. Charts were reviewed and the following information was recorded: discipline of referring physician, demographics, psychiatric diagnosis, referred individual’s and partner’s (if applicable) family history, and any current pregnancy history. Data were characterized using descriptive statistics. Results Between 1968 and 2007, 288 referrals were made for a primary indication of schizophrenia. Most referrals were made: (a) for individuals who had a first-degree family member with schizophrenia, rather than for affected individuals, (b) for preconception counseling, and (c) by family physicians (69%), with only 2% by psychiatrists. Conclusions In British Columbia, individuals affected with schizophrenia and their family members are rarely referred for psychiatric genetic counseling. There is a need to identify barriers to psychiatric genetic counseling and develop strategies to improve access. PMID:20034078

The impact of genetics on future drug discovery in schizophrenia.

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Matsumoto, Mitsuyuki; Walton, Noah M; Yamada, Hiroshi; Kondo, Yuji; Marek, Gerard J; Tajinda, Katsunori

2017-07-01

Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations. Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs. Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

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2011-01-01

Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

A genetic deconstruction of neurocognitive traits in schizophrenia and bipolar disorder.

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Carla P D Fernandes

Full Text Available Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders.Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium.The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope.Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders.

Associations between polygenic risk for schizophrenia and brain function during probabilistic learning in healthy individuals.

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Lancaster, Thomas M; Ihssen, Niklas; Brindley, Lisa M; Tansey, Katherine E; Mantripragada, Kiran; O'Donovan, Michael C; Owen, Michael J; Linden, David E J

2016-02-01

A substantial proportion of schizophrenia liability can be explained by additive genetic factors. Risk profile scores (RPS) directly index risk using a summated total of common risk variants weighted by their effect. Previous studies suggest that schizophrenia RPS predict alterations to neural networks that support working memory and verbal fluency. In this study, we apply schizophrenia RPS to fMRI data to elucidate the effects of polygenic risk on functional brain networks during a probabilistic-learning neuroimaging paradigm. The neural networks recruited during this paradigm have previously been shown to be altered to unmedicated schizophrenia patients and relatives of schizophrenia patients, which may reflect genetic susceptibility. We created schizophrenia RPS using summary data from the Psychiatric Genetic Consortium (Schizophrenia Working Group) for 83 healthy individuals and explore associations between schizophrenia RPS and blood oxygen level dependency (BOLD) during periods of choice behavior (switch-stay) and reflection upon choice outcome (reward-punishment). We show that schizophrenia RPS is associated with alterations in the frontal pole (PWHOLE-BRAIN-CORRECTED  = 0.048) and the ventral striatum (PROI-CORRECTED  = 0.036), during choice behavior, but not choice outcome. We suggest that the common risk variants that increase susceptibility to schizophrenia can be associated with alterations in the neural circuitry that support the processing of changing reward contingencies. Hum Brain Mapp 37:491-500, 2016. © 2015 Wiley Periodicals, Inc. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Genetic Variation in Schizophrenia Liability is Shared With Intellectual Ability and Brain Structure

NARCIS (Netherlands)

Bohlken, Marc M; Brouwer, Rachel M; Mandl, René C W; Kahn, René S; Hulshoff Pol, Hilleke E

2016-01-01

BACKGROUND: Alterations in intellectual ability and brain structure are important genetic markers for schizophrenia liability. How variations in these phenotypes interact with variance in schizophrenia liability due to genetic or environmental factors is an area of active investigation. Studying

Identification of a herpes simplex labialis susceptibility region on human chromosome 21.

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Hobbs, Maurine R; Jones, Brandt B; Otterud, Brith E; Leppert, Mark; Kriesel, John D

2008-02-01

Most of the United States population is infected with either herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, or both. Reactivations of HSV-1 infection cause herpes simplex labialis (HSL; cold sores or fever blisters), which is the most common recurring viral infection in humans. To investigate the possibility of a human genetic component conferring resistance or susceptibility to cold sores (i.e., a HSL susceptibility gene), we conducted a genetic linkage analysis that included serotyping and phenotyping 421 individuals from 39 families enrolled in the Utah Genetic Reference Project. Linkage analysis identified a 2.5-Mb nonrecombinant region of interest on the long arm of human chromosome 21, with a multipoint logarithm of odds score of 3.9 noted near marker abmc65 (D21S409). Nonparametric linkage analysis of the data also provided strong evidence for linkage (P = .0005). This region of human chromosome 21 contains 6 candidate genes for herpes susceptibility. The development of frequent cold sores is associated with a region on the long arm of human chromosome 21. This region contains several candidate genes that could influence the frequency of outbreaks of HSL.

A comprehensive family-based replication study of schizophrenia genes

DEFF Research Database (Denmark)

Aberg, Karolina A; Liu, Youfang; Bukszár, Jozsef

2013-01-01

Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets....

Animal models of gene-environment interactions in schizophrenia.

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Ayhan, Yavuz; Sawa, Akira; Ross, Christopher A; Pletnikov, Mikhail V

2009-12-07

The pathogenesis of schizophrenia and related mental illnesses likely involves multiple interactions between susceptibility genes of small effects and environmental factors. Gene-environment interactions occur across different stages of neurodevelopment to produce heterogeneous clinical and pathological manifestations of the disease. The main obstacle for mechanistic studies of gene-environment interplay has been the paucity of appropriate experimental systems for elucidating the molecular pathways that mediate gene-environment interactions relevant to schizophrenia. Recent advances in psychiatric genetics and a plethora of experimental data from animal studies allow us to suggest a new approach to gene-environment interactions in schizophrenia. We propose that animal models based on identified genetic mutations and measurable environment factors will help advance studies of the molecular mechanisms of gene-environment interplay.

Schizophrenia genetic variants are not associated with intelligence

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Van Scheltinga, A.F.T.; Bakker, S.C.; Van Haren, N.E.M.

2013-01-01

BACKGROUND: Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs......) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data...... significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p = 0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R 2 = 0.055, p = 2.1 × 10-7) and with IQ in the entire sample (R 2 = 0.018, p = 0.0008) but the effect on IQ...

Association analysis of 94 candidate genes and schizophrenia-related endophenotypes.

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Tiffany A Greenwood

Full Text Available While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI, P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility

Evidence for regional hippocampal damage in patients with schizophrenia

International Nuclear Information System (INIS)

Singh, Sadhana; Khushu, Subash; Kumar, Pawan; Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N.

2018-01-01

Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ( 1 H MRS) procedures. 1 H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

Evidence for regional hippocampal damage in patients with schizophrenia

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Singh, Sadhana; Khushu, Subash; Kumar, Pawan [DRDO, NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi (India); Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N. [RML Hospital, Post Graduate Institute of Medical Education and Research (PGIMER), New Delhi (India)

2018-02-15

Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ({sup 1}H MRS) procedures. {sup 1}H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia.

Science.gov (United States)

Kochunov, Peter; Ganjgahi, Habib; Winkler, Anderson; Kelly, Sinead; Shukla, Dinesh K; Du, Xiaoming; Jahanshad, Neda; Rowland, Laura; Sampath, Hemalatha; Patel, Binish; O'Donnell, Patricio; Xie, Zhiyong; Paciga, Sara A; Schubert, Christian R; Chen, Jian; Zhang, Guohao; Thompson, Paul M; Nichols, Thomas E; Hong, L Elliot

2016-12-01

Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brain's white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age-related decline in FA values. In the largest mega-analysis to date, we tested if differences in the trajectories of WM tract development influenced patient-control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging. Three cohorts of schizophrenia patients (total n = 177) and controls (total n = 249; age = 18-61 years) were ascertained with three 3T Siemens MRI scanners. Whole-brain and regional FA values were extracted using ENIGMA-DTI protocols. Statistics were evaluated using mega- and meta-analyses to detect effects of diagnosis and age-by-diagnosis interactions. In mega-analysis of whole-brain averaged FA, schizophrenia patients had lower FA (P = 10 -11 ) and faster age-related decline in FA (P = 0.02) compared with controls. Tract-specific heterochronicity measures, that is, abnormal rates of adolescent maturation and aging explained approximately 50% of the regional variance effects of diagnosis and age-by-diagnosis interaction in patients. Interactive, three-dimensional visualization of the results is available at www.enigma-viewer.org. WM tracts that mature later in life appeared more sensitive to the pathophysiology of schizophrenia and were more susceptible to faster age-related decline in FA values. Hum Brain Mapp 37:4673-4688, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Genetic susceptibility to Grave's disease.

Science.gov (United States)

Li, Hong; Chen, Qiuying

2013-06-01

The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept

NARCIS (Netherlands)

Franke, Barbara; Stein, Jason L.; Ripke, Stephan; Anttila, Verneri; Hibar, Derrek P.; van Hulzen, Kimm J. E.; Arias-Vasquez, Alejandro; Smoller, Jordan W.; Nichols, Thomas E.; Neale, Michael C.; McIntosh, Andrew M.; Lee, Phil; McMahon, Francis J.; Meyer-Lindenberg, Andreas; Mattheisen, Manuel; Andreassen, Ole A.; Gruber, Oliver; Sachdev, Perminder S.; Roiz-Santiañez, Roberto; Saykin, Andrew J.; Ehrlich, Stefan; Mather, Karen A.; Turner, Jessica A.; Schwarz, Emanuel; Thalamuthu, Anbupalam; Yao, Yin; Ho, Yvonne Y. W.; Martin, Nicholas G.; Wright, Margaret J.; O'Donovan, Michael C.; Thompson, Paul M.; Neale, Benjamin M.; Medland, Sarah E.; Sullivan, Patrick F.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William F.; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Chan, Raymond C. K.; Chen, Eric Y. H.; Chen, Ronald Y. L.; Cheng, Wei; Cheung, Eric F. C.; Chong, Siow Ann; Cloninger, C. Robert; Cohen, David; Cohen, Nadine; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L.; Degenhardt, Franziska; del Favero, Jurgen; DeLisi, Lynn E.; Demontis, Ditte; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedman, Joseph I.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Gopal, Srihari; Gratten, Jacob; de Haan, Lieuwe; Hammer, Christian; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan L.; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Hollegaard, Mads V.; Hougaard, David M.; Ikeda, Masashi; Joa, Inge; Julià, Antonio; Kähler, Anna K.; Kahn, René S.; Kalaydjieva, Luba; Karachanak-Yankova, Sena; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Khrunin, Andrey; Kim, Yunjung; Klovins, Janis; Knowles, James A.; Konte, Bettina; Kucinskas, Vaidutis; Kucinskiene, Zita Ausrele; Kuzelova-Ptackova, Hana; Laurent, Claudine; Lee, S. Hong; Keong, Jimmy Lee Chee; Legge, Sophie E.; Lerer, Bernard; Li, Miaoxin; Li, Tao; Liang, Kung-Yee; Lieberman, Jeffrey; Limborska, Svetlana; Lönnqvist, Jouko; Loughland, Carmel M.; Lubinski, Jan; Macek, Milan; Magnusson, Patrik K. E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Marsal, Sara; Mattingsdal, Morten; McCarley, Robert W.; McDonald, Colm; Meier, Sandra; Meijer, Carin J.; Melegh, Bela; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Mors, Ole; Müller-Myhsok, Bertram; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Nelis, Mari; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nikitina-Zake, Liene; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; O'Neill, F. Anthony; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Papiol, Sergi; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Perkins, Diana O.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Schall, Ulrich; Schubert, Christian R.; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Silverman, Jeremy M.; Sim, Kang; Slominsky, Petr; So, Hon-Cheong; Söderman, Erik; Spencer, Chris C. A.; Stahl, Eli A.; Stogmann, Elisabeth; Straub, Richard E.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Subramaniam, Mythily; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Thirumalai, Srinivas; Toncheva, Draga; Tooney, Paul A.; Veijola, Juha; Waddington, John; Walsh, Dermot; Wang, Dai; Wang, Qiang; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wong, Emily H. M.; Wormley, Brandon K.; Wu, Jing Qin; Xi, Hualin Simon; Zai, Clement C.; Zheng, Xuebin; Zimprich, Fritz; Wray, Naomi R.; Visscher, Peter M.; Adolfsson, Rolf; Blackwood, Douglas H. R.; Børglum, Anders D.; Bramon, Elvira; Buxbaum, Joseph D.; Cichon, Sven; Darvasi, Ariel; Domenici, Enrico; Ehrenreich, Hannelore; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G.; Kendler, Kenneth S.; Kirov, George; Knight, Jo; Lencz, Todd; Levinson, Douglas F.; Li, Qingqin S.; Liu, Jianjun; Malhotra, Anil K.; McCarroll, Steven A.; McQuillin, Andrew; Moran, Jennifer L.; Mortensen, Preben B.; Mowry, Bryan J.; Nöthen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sham, Pak C.; Sklar, Pamela; Clair, David St; Weinberger, Daniel R.; Wendland, Jens R.; Werge, Thomas; Daly, Mark J.; Renteria, Miguel E.; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Loohuis, Loes M. Olde; Luciano, Michelle; Macare, Christine; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn; Heister, Angelien J. G. A. M.; Höhn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, David R.; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nilsson, Lars G.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Toga, Arthur W.; Traynor, Bryan; Troncoso, Juan; Hernández, Maria C. Valdés; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; Williams, Robert W.; Brunner, Han G.; Buitelaar, Jan K.; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; LeHellard, Stephanie; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Sisodiya, Sanjay M.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Luting, Xue; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Schumann, Gunter

2016-01-01

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use

A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes

DEFF Research Database (Denmark)

de Jong, Simone; Boks, Marco P M; Fuller, Tova F

2012-01-01

Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood...... of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co......, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes...

Genetic liability for schizophrenia predicts risk of immune disorders

NARCIS (Netherlands)

Stringer, Sven; Kahn, René S.; de Witte, Lot D.; Ophoff, Roel A.; Derks, Eske M.

2014-01-01

Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap between

Genetic liability for schizophrenia predicts risk of immune disorders

NARCIS (Netherlands)

Stringer, Sven; Kahn, René S; de Witte, Lot D; Ophoff, Roel A; Derks, Eske M

2014-01-01

BACKGROUND: Schizophrenia patients and their parents have an increased risk of immune disorders compared to population controls and their parents. This may be explained by genetic overlap in the pathogenesis of both types of disorders. The purpose of this study was to investigate the genetic overlap

New genetic findings in schizophrenia: is there still room for the dopamine hypothesis of schizophrenia?

Directory of Open Access Journals (Sweden)

Vanessa Nieratschker

2010-05-01

Full Text Available Schizophrenia is a highly heritable disorder, but the identification of specific genes has proven to be a difficult endeavour. Genes involved in the dopaminergic system are considered to be major candidates since the “dopamine hypothesis” of impairment in dopaminergic neurotransmission is one of the most widely accepted hypotheses of the aetiology of schizophrenia. The overall findings from candidate studies do provide some support for the “dopamine hypothesis”. However, results from the first systematic genome-wide association (GWA studies have implicated variants within ZNF804A, NRGN, TCF4, and variants in the MHC region on chromosome 6p22.1. Although these genes may not immediately impact on dopaminergic neurotransmission, it remains possible that downstream impairments in dopaminergic function are caused. Furthermore, only a very small fraction of all truly associated genetic variants have been detected and many more associated variants will be identified in the future by GWA studies and alternative approaches. The results of these studies may allow a more comprehensive re-evaluation of the dopamine hypothesis.

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes.

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Rohde, Palle Duun; Demontis, Ditte; Cuyabano, Beatriz Castro Dias; Børglum, Anders D; Sørensen, Peter

2016-08-01

Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited power to detect genetic markers with small effects. Instead, aggregating genetic markers based on biological information might increase the power to identify sets of genetic markers of etiological significance. Several set test methods have been proposed: Here we propose a new set test derived from genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case-control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism and immunological responses, which previously have been implicated with schizophrenia based on experimental and observational studies. Copyright © 2016 by the Genetics Society of America.

Molecular genetics of schizophrenia: past, present and future

Indian Academy of Sciences (India)

Unknown

leucocyte antigen; IDDM, insulin dependent diabetes mellitus; MAO, monoamine oxidase; MHC, ... In this review, we summarize the evolution of schizophrenia genetics from ...... K, Yeh J I and Hsiao K J 1999 Systematic mutation analysis.

Hopes and Expectations Regarding Genetic Testing for Schizophrenia Among Young Adults at Clinical High-Risk for Psychosis.

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Friesen, Phoebe; Lawrence, Ryan E; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

2016-11-01

Genetic tests for schizophrenia could introduce both risks and benefits. Little is known about the hopes and expectations of young adults at clinical high-risk for psychosis concerning genetic testing for schizophrenia, despite the fact that these youth could be among those highly affected by such tests. We conducted semistructured interviews with 15 young adults at clinical high-risk for psychosis to ask about their interest, expectations, and hopes regarding genetic testing for schizophrenia. Most participants reported a high level of interest in genetic testing for schizophrenia, and the majority said they would take such a test immediately if it were available. Some expressed far-reaching expectations for a genetic test, such as predicting symptom severity and the timing of symptom onset. Several assumed that genetic testing would be accompanied by interventions to prevent schizophrenia. Participants anticipated mixed reactions on finding out they had a genetic risk for schizophrenia, suggesting that they might feel both a sense of relief and a sense of hopelessness. We suggest that genetic counseling could play an important role in counteracting a culture of genetic over-optimism and helping young adults at clinical high-risk for psychosis understand the limitations of genetic testing. Counseling sessions could also invite individuals to explore how receiving genetic risk information might impact their well-being, as early evidence suggests that some psychological factors help individuals cope, whereas others heighten distress related to genetic test results.

Identification of Genetic Factors in the Etiology of Schizophrenia

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Argel Aguilar Valles

2011-09-01

Full Text Available ABSTRACT Schizophrenia is a mental disorder that affects approximately 1% of the worldwide population. It is characterized by psychotic episodes in which individuals have hallucinations or delusions. This disorder also involves a strong element of social dysfunction, lack of motivation and profound cognitive deficits. The causes of this disorder remain largely unknown, but evidence indicates that arises from changes in the development of the central nervous system. Among the identified risk factors for this disorder are several environmental events, including prenatal infections and malnutrition, and complications during childbirth. However, the most important factor seems to be genetics. Despite this, the identification of genes involved in the development of this disorder has emerged as one of the most difficult tasks facing modern genetics and genomics. The development of techniques for studying the human genome has allowed a more systematic approach to determine variations in the genome sequence and structure that area casually involved in schizophrenia. These studies suggest the participation hundreds of genes in schizophrenia development. In addition, it has been suggested that many of these genes are involved in various mental illnesses that today are diagnosed as separate entities, but whose biological substrate may be shared. Key words: schizophrenia, deletions, development, duplications, polymorphisms.

Decreased left middle temporal gyrus volume in antipsychotic drug-naive, first-episode schizophrenia patients and their healthy unaffected siblings.

Science.gov (United States)

Hu, Maorong; Li, Jun; Eyler, Lisa; Guo, Xiaofeng; Wei, Qingling; Tang, Jingsong; Liu, Feng; He, Zhong; Li, Lihua; Jin, Hua; Liu, Zhening; Wang, Juan; Liu, Fang; Chen, Huafu; Zhao, Jingping

2013-03-01

The shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover gray matter volume differences in patients with schizophrenia and their unaffected siblings with voxel-based morphometry (VBM). We recruited antipsychotic drug-naive, first-episode schizophrenia (FES) patients, their unaffected siblings and age-, sex- and handedness-matched healthy controls. We used VBM to investigate differences in gray matter volume among the 3 groups. There were significant gray matter volumetric differences among the 3 groups in bilateral hippocampal and parahippocampal gyri, bilateral middle temporal gyri, and superior temporal gyri (FDR ptemporal gyrus, and volume of this region was not different between siblings and patients. Our findings confirm and extend previous VBM analyses in schizophrenia and it indicate that schizophrenia may be characterized by an abnormal development of cerebral lateralization. Furthermore, these data argue that patients and their unaffected siblings might share decreases in the gray matter volume of the left middle temporal gyrus, and this regional reduction might be a potential endophenotype for schizophrenia. Copyright © 2013 Elsevier B.V. All rights reserved.

Molecular genetic gene-environment studies using candidate genes in schizophrenia: a systematic review.

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Modinos, Gemma; Iyegbe, Conrad; Prata, Diana; Rivera, Margarita; Kempton, Matthew J; Valmaggia, Lucia R; Sham, Pak C; van Os, Jim; McGuire, Philip

2013-11-01

The relatively high heritability of schizophrenia suggests that genetic factors play an important role in the etiology of the disorder. On the other hand, a number of environmental factors significantly influence its incidence. As few direct genetic effects have been demonstrated, and there is considerable inter-individual heterogeneity in the response to the known environmental factors, interactions between genetic and environmental factors may be important in determining whether an individual develops the disorder. To date, a considerable number of studies of gene-environment interactions (G×E) in schizophrenia have employed a hypothesis-based molecular genetic approach using candidate genes, which have led to a range of different findings. This systematic review aims to summarize the results from molecular genetic candidate studies and to review challenges and opportunities of this approach in psychosis research. Finally, we discuss the potential of future prospects, such as new studies that combine hypothesis-based molecular genetic candidate approaches with agnostic genome-wide association studies in determining schizophrenia risk. © 2013 Elsevier B.V. All rights reserved.

Schizophrenia with the 22q11.2 deletion and additional genetic defects: case history.

Science.gov (United States)

Toyosima, M; Maekawa, M; Toyota, T; Iwayama, Y; Arai, M; Ichikawa, T; Miyashita, M; Arinami, T; Itokawa, M; Yoshikawa, T

2011-09-01

The 22q11.2 deletion is the most prominent known genetic risk factor for schizophrenia, but its penetrance is at most approximately 50% suggesting that additional risk factors are required for disease progression. We examined a woman with schizophrenia with this deletion for such risk factors. She had high plasma pentosidine levels ('carbonyl stress') and a frameshift mutation in the responsible gene, GLO1. She also had a constant exotropia, so we examined the PHOX2B gene associated with both schizophrenia and strabismus, and detected a 5-alanine deletion. We propose that the combination of these genetic defects may have exceeded the threshold for the manifestation of schizophrenia.

[Schizophrenia, environment and epigenetics].

Science.gov (United States)

Must, Anita; Janka, Zoltan; Horvath, Szatmar

2011-12-01

Psychotic, cognitive and affective symptoms defining schizophrenia may, though much less severe, manifest themselves in up to 10 to 20% of the general population. What explains the fact that in certain cases the symptoms require even constant medical supervision, while others are capable of living a normal life within social conventions? Which factors lead to the transition of mild, subclinical manifestations and vulnerability indicators towards the outburst of one of the most severe and depriving mental disorders? Genetic susceptibility is undoubtedly crucial. More recent research findings emphasize the modifying effect of specific environmental factors on gene expression. The gene-environment interplay may induce so-called epigenetic alterations which may manifest themselves over several generations. Future integrative, multi-dimensional and flexible schizophrenia research approaches focusing on the identification of neurobiological and cognitive outcomes are much needed to understand disease vulnerability, susceptibility mechanisms, periods and interactions. Research methods may differ, but our aim is common - establishing more effective diagnostic and therapeutic interventions.

A major genetic component of BSE susceptibility

Science.gov (United States)

Juling, Katrin; Schwarzenbacher, Hermann; Williams, John L; Fries, Ruedi

2006-01-01

Background Coding variants of the prion protein gene (PRNP) have been shown to be major determinants for the susceptibility to transmitted prion diseases in humans, mice and sheep. However, to date, the effects of polymorphisms in the coding and regulatory regions of bovine PRNP on bovine spongiform encephalopathy (BSE) susceptibility have been considered marginal or non-existent. Here we analysed two insertion/deletion (indel) polymorphisms in the regulatory region of bovine PRNP in BSE affected animals and controls of four independent cattle populations from UK and Germany. Results In the present report, we show that two previously reported 23- and 12-bp insertion/deletion (indel) polymorphisms in the regulatory region of bovine PRNP are strongly associated with BSE incidence in cattle. Genotyping of BSE-affected and control animals of UK Holstein, German Holstein, German Brown and German Fleckvieh breeds revealed a significant overrepresentation of the deletion alleles at both polymorphic sites in diseased animals (P = 2.01 × 10-3 and P = 8.66 × 10-5, respectively). The main effect on susceptibility is associated with the 12-bp indel polymorphism. Compared with non-carriers, heterozygous and homozygous carriers of the 12-bp deletion allele possess relatively higher risks of having BSE, ranging from 1.32 to 4.01 and 1.74 to 3.65 in the different breeds. These values correspond to population attributable risks ranging from 35% to 53%. Conclusion Our results demonstrate a substantial genetic PRNP associated component for BSE susceptibility in cattle. Although the BSE risk conferred by the deletion allele of the 12-bp indel in the regulatory region of PRNP is substantial, the main risk factor for BSE in cattle is environmental, i.e. exposure to feedstuffs contaminated with the infectious agent. PMID:17014722

A major genetic component of BSE susceptibility

Directory of Open Access Journals (Sweden)

Williams John L

2006-10-01

Full Text Available Abstract Background Coding variants of the prion protein gene (PRNP have been shown to be major determinants for the susceptibility to transmitted prion diseases in humans, mice and sheep. However, to date, the effects of polymorphisms in the coding and regulatory regions of bovine PRNP on bovine spongiform encephalopathy (BSE susceptibility have been considered marginal or non-existent. Here we analysed two insertion/deletion (indel polymorphisms in the regulatory region of bovine PRNP in BSE affected animals and controls of four independent cattle populations from UK and Germany. Results In the present report, we show that two previously reported 23- and 12-bp insertion/deletion (indel polymorphisms in the regulatory region of bovine PRNP are strongly associated with BSE incidence in cattle. Genotyping of BSE-affected and control animals of UK Holstein, German Holstein, German Brown and German Fleckvieh breeds revealed a significant overrepresentation of the deletion alleles at both polymorphic sites in diseased animals (P = 2.01 × 10-3 and P = 8.66 × 10-5, respectively. The main effect on susceptibility is associated with the 12-bp indel polymorphism. Compared with non-carriers, heterozygous and homozygous carriers of the 12-bp deletion allele possess relatively higher risks of having BSE, ranging from 1.32 to 4.01 and 1.74 to 3.65 in the different breeds. These values correspond to population attributable risks ranging from 35% to 53%. Conclusion Our results demonstrate a substantial genetic PRNP associated component for BSE susceptibility in cattle. Although the BSE risk conferred by the deletion allele of the 12-bp indel in the regulatory region of PRNP is substantial, the main risk factor for BSE in cattle is environmental, i.e. exposure to feedstuffs contaminated with the infectious agent.

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function.

Science.gov (United States)

Smeland, Olav B; Frei, Oleksandr; Kauppi, Karolina; Hill, W David; Li, Wen; Wang, Yunpeng; Krull, Florian; Bettella, Francesco; Eriksen, Jon A; Witoelar, Aree; Davies, Gail; Fan, Chun C; Thompson, Wesley K; Lam, Max; Lencz, Todd; Chen, Chi-Hua; Ueland, Torill; Jönsson, Erik G; Djurovic, Srdjan; Deary, Ian J; Dale, Anders M; Andreassen, Ole A

2017-10-01

Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction. To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains. Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888). Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined. Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and

Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.

Science.gov (United States)

Rampino, Antonio; Walker, Rosie May; Torrance, Helen Scott; Anderson, Susan Maguire; Fazio, Leonardo; Di Giorgio, Annabella; Taurisano, Paolo; Gelao, Barbara; Romano, Raffaella; Masellis, Rita; Ursini, Gianluca; Caforio, Grazia; Blasi, Giuseppe; Millar, J Kirsty; Porteous, David John; Thomson, Pippa Ann; Bertolino, Alessandro; Evans, Kathryn Louise

2014-01-01

Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1), a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.

Expression of DISC1-interactome members correlates with cognitive phenotypes related to schizophrenia.

Directory of Open Access Journals (Sweden)

Antonio Rampino

Full Text Available Cognitive dysfunction is central to the schizophrenia phenotype. Genetic and functional studies have implicated Disrupted-in-Schizophrenia 1 (DISC1, a leading candidate gene for schizophrenia and related psychiatric conditions, in cognitive function. Altered expression of DISC1 and DISC1-interactors has been identified in schizophrenia. Dysregulated expression of DISC1-interactome genes might, therefore, contribute to schizophrenia susceptibility via disruption of molecular systems required for normal cognitive function. Here, the blood RNA expression levels of DISC1 and DISC1-interacting proteins were measured in 63 control subjects. Cognitive function was assessed using neuropsychiatric tests and functional magnetic resonance imaging was used to assess the activity of prefrontal cortical regions during the N-back working memory task, which is abnormal in schizophrenia. Pairwise correlations between gene expression levels and the relationship between gene expression levels and cognitive function and N-back-elicited brain activity were assessed. Finally, the expression levels of DISC1, AKAP9, FEZ1, NDEL1 and PCM1 were compared between 63 controls and 69 schizophrenic subjects. We found that DISC1-interactome genes showed correlated expression in the blood of healthy individuals. The expression levels of several interactome members were correlated with cognitive performance and N-back-elicited activity in the prefrontal cortex. In addition, DISC1 and NDEL1 showed decreased expression in schizophrenic subjects compared to healthy controls. Our findings highlight the importance of the coordinated expression of DISC1-interactome genes for normal cognitive function and suggest that dysregulated DISC1 and NDEL1 expression might, in part, contribute to susceptibility for schizophrenia via disruption of prefrontal cortex-dependent cognitive functions.

The Role of Inflammation in Schizophrenia

Directory of Open Access Journals (Sweden)

Norbert eMüller

2015-10-01

Full Text Available AbstractHigh levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA system and other immune functions. Another line of evidence demonstrates that chronic (disstress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis

Covariance Association Test (CVAT) Identifies Genetic Markers Associated with Schizophrenia in Functionally Associated Biological Processes

DEFF Research Database (Denmark)

Rohde, Palle Duun; Demontis, Ditte; Castro Dias Cuyabano, Beatriz

2016-01-01

was among the top performers. When extending CVAT to utilize a mixture of SNP effects, we found an increase in power to detect the causal sets. Applying the methods to a Danish schizophrenia case–control data set, we found genomic evidence for association of schizophrenia with vitamin A metabolism......Schizophrenia is a psychiatric disorder with large personal and social costs, and understanding the genetic etiology is important. Such knowledge can be obtained by testing the association between a disease phenotype and individual genetic markers; however, such single-marker methods have limited...... genomic best linear unbiased prediction (GBLUP), the covariance association test (CVAT). We compared the performance of CVAT to other commonly used set tests. The comparison was conducted using a simulated study population having the same genetic parameters as for schizophrenia. We found that CVAT...

fMRI study of language activation in schizophrenia, schizoaffective disorder and in individuals genetically at high risk.

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Li, Xiaobo; Branch, Craig A; Ardekani, Babak A; Bertisch, Hilary; Hicks, Chindo; DeLisi, Lynn E

2007-11-01

Structural and functional abnormalities have been found in language-related brain regions in patients with schizophrenia. We previously reported findings pointing to differences in word processing between people with schizophrenia and individuals who are at high-risk for schizophrenia using a voxel-based (whole brain) fMRI approach. We now extend this finding to specifically examine functional activity in three language related cortical regions using a larger cohort of individuals. A visual lexical discrimination task was performed by 36 controls, 21 subjects at high genetic-risk for schizophrenia, and 20 patients with schizophrenia during blood oxygenation level dependent (BOLD) fMRI scanning. Activation in bilateral inferior frontal gyri (Brodmann's area 44-45), bilateral inferior parietal lobe (Brodmann's area 39-40), and bilateral superior temporal gyri (Brodmann's area 22) was investigated. For all subjects, two-tailed Pearson correlations were calculated between the computed laterality index and a series of cognitive test scores determining language functioning. Regional activation in Brodmann's area 44-45 was left lateralized in normal controls, while high-risk subjects and patients with schizophrenia or schizoaffective disorder showed more bilateral activation. No significant differences among the three diagnostic groups in the other two regions of interest (Brodmann's area 22 or areas 39-40) were found. Furthermore, the apparent reasons for loss of leftward language lateralization differed between groups. In high-risk subjects, the loss of lateralization was based on reduced left hemisphere activation, while in the patient group, it was due to increased right side activation. Language ability related cognitive scores were positively correlations with the laterality indices obtained from Brodmann's areas 44-45 in the high-risk group, and with the laterality indices from Brodmann's areas 22 and 44-45 in the patient group. This study reinforces previous

Genetic underpinnings of left superior temporal gyrus thickness in patients with schizophrenia.

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Wolthusen, Rick P F; Hass, Johanna; Walton, Esther; Turner, Jessica A; Rössner, Veit; Sponheim, Scott R; Ho, Beng-Choon; Holt, Daphne J; Gollub, Randy L; Calhoun, Vince; Ehrlich, Stefan

2015-08-07

Schizophrenia is a highly disabling psychiatric disorder with a heterogeneous phenotypic appearance. We aimed to further the understanding of some of the underlying genetics of schizophrenia, using left superior temporal gyrus (STG) grey matter thickness reduction as an endophenoptype in a genome-wide association (GWA) study. Structural magnetic resonance imaging (MRI) and genetic data of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia were used to analyse the interaction effects between 1,067,955 single nucleotide polymorphisms (SNPs) and disease status on left STG thickness in 126 healthy controls and 113 patients with schizophrenia. We next used a pathway approach to detect underlying pathophysiological pathways that may be related to schizophrenia. No SNP by diagnosis interaction effect reached genome-wide significance (5 × 10 -8 ) in our GWA study, but 10 SNPs reached P-values less than 10 -6 . The most prominent pathways included those involved in insulin, calcium, PI3K-Akt and MAPK signalling. Our strongest findings in the GWA study and pathway analysis point towards an involvement of glucose metabolism in left STG thickness reduction in patients with schizophrenia only. These results are in line with recently published studies, which showed an increased prevalence of psychosis among patients with metabolic syndrome-related illnesses including diabetes.

Factor structure and heritability of endophenotypes in schizophrenia: findings from the Consortium on the Genetics of Schizophrenia (COGS-1).

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Seidman, Larry J; Hellemann, Gerhard; Nuechterlein, Keith H; Greenwood, Tiffany A; Braff, David L; Cadenhead, Kristin S; Calkins, Monica E; Freedman, Robert; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Olincy, Ann; Radant, Allen D; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Green, Michael F

2015-04-01

Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements. The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=83), their nonpsychotic siblings (n=151), and community comparison subjects (n=209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR. Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction). Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification of genetic factors in the etiology of schizophrenia

International Nuclear Information System (INIS)

Aguilar Valles, Argel

2011-01-01

Schizophrenia is a mental disorder that affects approximately 1% of the worldwide population. It is characterized by psychotic episodes in which individuals have hallucinations or delusions. This disorder also involves a strong element of social dysfunction, lack of motivation and profound cognitive deficits. The causes of this disorder remain largely unknown, but evidence indicates that arises from changes in the development of the central nervous system. Among the identified risk factors for this disorder are several environmental events, including prenatal infections and malnutrition, and complications during childbirth. However, the most important factor seems to be genetics. Despite this, the identification of genes involved in the development of this disorder has emerged as one of the most difficult tasks facing modern genetics and genomics. The development of techniques for studying the human genome has allowed a more systematic approach to determine variations in the genome sequence and structure that area casually involved in schizophrenia. These studies suggest the participation of hundreds of genes in schizophrenia development. In addition, it has been suggested that many of these genes are involved in various mental illnesses that today are diagnosed as separate entities, but whose biological substrate may be shared.

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia.

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Perez, Stephanie M; Aguilar, David D; Neary, Jennifer L; Carless, Melanie A; Giuffrida, Andrea; Lodge, Daniel J

2016-01-01

Both environmental and genetic factors contribute to schizophrenia; however, the exact etiology of this disorder is not known. Animal models are utilized to better understand the mechanisms associated with neuropsychiatric diseases, including schizophrenia. One of these involves gestational administration of methylazoxymethanol acetate (MAM) to induce a developmental disruption, which in turn produces a schizophrenia-like phenotype in post-pubertal rats. The mechanisms by which MAM produces this phenotype are not clear; however, we now demonstrate that MAM induces differential DNA methylation, which may be heritable. Here we demonstrate that a subset of both second (F2) and third (F3) filial generations of MAM-treated rats displays a schizophrenia-like phenotype and hypermethylation of the transcription factor, Sp5. Specifically, ventral tegmental area of dopamine neuron activity was examined using electrophysiology as a correlate for the dopamine hyperfunction thought to underlie psychosis in patients. Interestingly, only a subset of F2 and F3 MAM rats exhibited increases in dopamine neuron population activity, indicating that this may be a unique model with a susceptibility to develop a schizophrenia-like phenotype. An increase in dopamine system function in rodent models has been previously associated with decreases in hippocampal GABAergic transmission. In line with these observations, we found a significant correlation between hippocampal parvalbumin expression and dopamine neuron activity in F2 rats. These data therefore provide evidence that offspring born from MAM-treated rats possess a susceptibility to develop aspects of a schizophrenia-like phenotype and may provide a useful tool to investigate gene-environment interactions.

Genetic susceptibility of periodontitis

NARCIS (Netherlands)

Laine, M.L.; Crielaard, W.; Loos, B.G.

2012-01-01

In this systematic review, we explore and summarize the peer-reviewed literature on putative genetic risk factors for susceptibility to aggressive and chronic periodontitis. A comprehensive literature search on the PubMed database was performed using the keywords ‘periodontitis’ or ‘periodontal

Genetic vulnerability and premature death in schizophrenia spectrum disorders: a 28-year follow-up of adoptees in the Finnish Adoptive Family Study of Schizophrenia.

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Hakko, Helinä; Wahlberg, Karl-Erik; Tienari, Pekka; Räsänen, Sami

2011-09-01

Excess mortality is widely reported among schizophrenia patients, but rarely examined in adoption study settings. We investigated whether genetic background plays a role in the premature death of adoptees with schizophrenia. Mortality among 382 adoptees in the Finnish Adoptive Family Study of Schizophrenia was monitored from 1977 to 2005 through the national causes-of-death register. The sample covered 190 adoptees with a high genetic risk of schizophrenia (HR) and 192 with a low risk (LR). Overall mortality among the adoptees did not differ between the HR and LR groups, as 10% and 9% respectively had died during the follow-up, at mean ages of 45 and 46 years. Schizophrenia spectrum disorder was the most significant predictor of premature death in both groups, with dysfunction in the rearing family environment associated with mortality, unnatural deaths and suicides in the HR but not in the LR group. All the suicides involved HR cases. Mortality among the adoptees was not related to genetic factors but to environmental ones. The association of unnatural deaths and suicides with dysfunction in the rearing environment among the HR adoptees may indicate that they had a greater genetically determined vulnerability to environmental effects than their LR counterparts. The genetic and rearing environments can be disentangled in this setting because the biological parents give the offspring their genes and the adoptive parents give them their rearing environment. Our findings add to knowledge of the factors associated with the premature death of adoptees in mid-life.

Genetics Home Reference: schizophrenia

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... Share: Email Facebook Twitter Home Health Conditions Schizophrenia Schizophrenia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Schizophrenia is a brain disorder classified as a psychosis, ...

Dysbindin-1 Involvement in the Etiology of Schizophrenia

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Haitao Wang

2017-09-01

Full Text Available Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world’s population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

Dysbindin-1 Involvement in the Etiology of Schizophrenia.

Science.gov (United States)

Wang, Haitao; Xu, Jiangping; Lazarovici, Philip; Zheng, Wenhua

2017-09-22

Schizophrenia is a major psychiatric disorder that afflicts about 1% of the world's population, falling into the top 10 medical disorders causing disability. Existing therapeutic strategies have had limited success on cognitive impairment and long-term disability and are burdened by side effects. Although new antipsychotic medications have been launched in the past decades, there has been a general lack of significant innovation. This lack of significant progress in the pharmacotherapy of schizophrenia is a reflection of the complexity and heterogeneity of the disease. To date, many susceptibility genes have been identified to be associated with schizophrenia. DTNBP1 gene, which encodes dysbindin-1, has been linked to schizophrenia in multiple populations. Studies on genetic variations show that DTNBP1 modulate prefrontal brain functions and psychiatric phenotypes. Dysbindin-1 is enriched in the dorsolateral prefrontal cortex and hippocampus, while postmortem brain studies of individuals with schizophrenia show decreased levels of dysbindin-1 mRNA and protein in these brain regions. These studies proposed a strong connection between dysbindin-1 function and the pathogenesis of disease. Dysbindin-1 protein was localized at both pre- and post-synaptic sites, where it regulates neurotransmitter release and receptors signaling. Moreover, dysbindin-1 has also been found to be involved in neuronal development. Reduced expression levels of dysbindin-1 mRNA and protein appear to be common in dysfunctional brain areas of schizophrenic patients. The present review addresses our current knowledge of dysbindin-1 with emphasis on its potential role in the schizophrenia pathology. We propose that dysbindin-1 and its signaling pathways may constitute potential therapeutic targets in the therapy of schizophrenia.

The Complement Control-Related Genes CSMD1 and CSMD2 Associate to Schizophrenia

DEFF Research Database (Denmark)

Håvik, Bjarte; Le Hellard, Stephanie; Rietschel, Marcella

2011-01-01

BACKGROUND: Patients with schizophrenia often suffer from cognitive dysfunction, including impaired learning and memory. We recently demonstrated that long-term potentiation in rat hippocampus, a mechanistic model of learning and memory, is linked to gene expression changes in immunity......-related processes involved in complement activity and antigen presentation. We therefore aimed to examine whether key regulators of these processes are genetic susceptibility factors in schizophrenia. METHODS: Analysis of genetic association was based on data mining of genotypes from a German genome......-wide association study and a multiplex GoldenGate tag single nucleotide polymorphism (SNP)-based assay of Norwegian and Danish case-control samples (Scandinavian Collaboration on Psychiatric Etiology), including 1133 patients with schizophrenia and 2444 healthy control subjects. RESULTS: Allelic associations were...

A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes.

Directory of Open Access Journals (Sweden)

Simone de Jong

Full Text Available Despite large-scale genome-wide association studies (GWAS, the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1, is located in, and regulated by the major histocompatibility (MHC complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network.

Genome-wide association study with the risk of schizophrenia in a Korean population.

Science.gov (United States)

Kim, Lyoung Hyo; Park, Byung Lae; Cheong, Hyun Sub; Namgoong, Suhg; Kim, Ji On; Kim, Jeong-Hyun; Shin, Joong-Gon; Park, Chul Soo; Kim, Bong-Jo; Kim, Jae Won; Choi, Ihn-Geun; Hwang, Jaeuk; Shin, Hyoung Doo; Woo, Sung-Il

2016-03-01

Schizophrenia is regarded as a multifactorial and polygenic brain disorder that is attributed to different combinations of genetic and environmental risk factors. Recently, several genome-wide association studies (GWASs) of schizophrenia have identified numerous risk factors, but the replication results remain controversial and ambiguous. To identify schizophrenia susceptibility loci in the Korean population, we performed a GWAS using the Illumina HumanOmni1-Quad V1.0 Microarray. We genotyped 1,140,419 single nucleotide polymorphisms (SNPs) in 350 Korea schizophrenia patients and 700 control subjects, and approximately 620,001 autosomal SNPs were passed our quality control. In the case-control analysis, the rs9607195 A>G on intergenic area 250 kb away from the ISX gene and the rs12738007 A>G on the intron of the MECR gene were the most strongly associated SNPs with the risk of schizophrenia (P = 6.2 × 10(-8) , OR = 0.50 and P = 3.7 × 10(-7) , OR = 2.39, respectively). In subsequent fine-mapping analysis, 6 SNPs of MECR were genotyped with 310 schizophrenia patients and 604 control subjects. The association of the MECR rs12738007, a top ranked-SNP in GWAS, was replicated (P = 1.5 × 10(-2) , OR = 1.53 in fine mapping analysis, P = 1.5 × 10(-6) , OR = 1.90 in combined analysis). The identification of putative schizophrenia susceptibility loci could provide new insights into genetic factors related with schizophrenia and clues for the development of diagnosis strategies. © 2015 Wiley Periodicals, Inc.

Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

Science.gov (United States)

Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

2016-01-01

Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study.

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Martin, Joanna; Tilling, Kate; Hubbard, Leon; Stergiakouli, Evie; Thapar, Anita; Davey Smith, George; O'Donovan, Michael C; Zammit, Stanley

2016-06-15

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991-2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1-15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Genetic evidence for the association between the early growth response 3 (EGR3 gene and schizophrenia.

Directory of Open Access Journals (Sweden)

Rui Zhang

Full Text Available Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3 gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ∼2.3 kb in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3 showed significant differences between cases and controls in both genotype frequency distribution (P = 0.016 and allele frequency distribution (P = 0.009. Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P = 0.0012; a significant difference was found for the common haplotype AG (P = 0.0005. Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P = 0.0001. In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis.

Schizophrenia.

Science.gov (United States)

Kahn, René S; Sommer, Iris E; Murray, Robin M; Meyer-Lindenberg, Andreas; Weinberger, Daniel R; Cannon, Tyrone D; O'Donovan, Michael; Correll, Christoph U; Kane, John M; van Os, Jim; Insel, Thomas R

2015-11-12

Schizophrenia is a chronic psychiatric disorder with a heterogeneous genetic and neurobiological background that influences early brain development, and is expressed as a combination of psychotic symptoms - such as hallucinations, delusions and disorganization - and motivational and cognitive dysfunctions. The mean lifetime prevalence of the disorder is just below 1%, but large regional differences in prevalence rates are evident owing to disparities in urbanicity and patterns of immigration. Although gross brain pathology is not a characteristic of schizophrenia, the disorder involves subtle pathological changes in specific neural cell populations and in cell-cell communication. Schizophrenia, as a cognitive and behavioural disorder, is ultimately about how the brain processes information. Indeed, neuroimaging studies have shown that information processing is functionally abnormal in patients with first-episode and chronic schizophrenia. Although pharmacological treatments for schizophrenia can relieve psychotic symptoms, such drugs generally do not lead to substantial improvements in social, cognitive and occupational functioning. Psychosocial interventions such as cognitive-behavioural therapy, cognitive remediation and supported education and employment have added treatment value, but are inconsistently applied. Given that schizophrenia starts many years before a diagnosis is typically made, the identification of individuals at risk and those in the early phases of the disorder, and the exploration of preventive approaches are crucial.

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties.

Science.gov (United States)

St Pourcain, B; Robinson, E B; Anttila, V; Sullivan, B B; Maller, J; Golding, J; Skuse, D; Ring, S; Evans, D M; Zammit, S; Fisher, S E; Neale, B M; Anney, R J L; Ripke, S; Hollegaard, M V; Werge, T; Ronald, A; Grove, J; Hougaard, D M; Børglum, A D; Mortensen, P B; Daly, M J; Davey Smith, G

2018-02-01

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.

New Genetic Susceptibility Factors for Sjögren's Syndrome Revealed

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... Spotlight on Research Spotlight on Research New Genetic Susceptibility Factors for Sjögren’s Syndrome Revealed By Kirstie Saltsman, ... swallowing and speaking. “The identification of these genetic susceptibility factors opens up new avenues for understanding how ...

Association of adoptive child's thought disorders and schizophrenia spectrum disorders with their genetic liability for schizophrenia spectrum disorders, season of birth and parental Communication Deviance.

Science.gov (United States)

Roisko, Riikka; Wahlberg, Karl-Erik; Hakko, Helinä; Tienari, Pekka

2015-04-30

Joint effects of genotype and the environment have turned out to be significant in the development of psychotic disorders. The purpose of the present study was to assess the association of an adoptive child׳s thought and schizophrenia spectrum disorders with genetic and environmental risk indicators and their interactions. A subgroup of the total sample used in the Finnish Adoptive Family Study was considered in the present study. The subjects were 125 adoptees at a high (n=53) or low (n=72) genetic risk of schizophrenia spectrum disorders and their adoptive parents. The risk factors evaluated were the adoptive child's genetic risk for schizophrenia spectrum disorders, winter or spring birth and parental Communication Deviance (CD). Thought disorders in the adoptees were assessed using the Thought Disorder Index and diagnoses were made according to DSM-III-R criteria. The adoptive child׳s Thought Disorder Index was only associated with parental Communication Deviance. The adoptive child's heightened genetic risk or winter or spring birth or parental CD or their interactions did not predict the adoptee's schizophrenia spectrum disorder. The results suggest that studies taking several risk indicators and their interactions into account may change views on the mutual significance of well-known risk factors. Copyright © 2015. Published by Elsevier Ireland Ltd.

Common variants conferring risk of schizophrenia

DEFF Research Database (Denmark)

Stefansson, Hreinn; Ophoff, Roel A; Steinberg, Stacy

2009-01-01

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease...... conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have.......2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition....

Pseudoautosomal region in schizophrenia: linkage analysis of seven loci by sib-pair and lod-score methods.

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d'Amato, T; Waksman, G; Martinez, M; Laurent, C; Gorwood, P; Campion, D; Jay, M; Petit, C; Savoye, C; Bastard, C

1994-05-01

In a previous study, we reported a nonrandom segregation between schizophrenia and the pseudoautosomal locus DXYS14 in a sample of 33 sibships. That study has been extended by the addition of 16 new sibships from 16 different families. Data from six other loci of the pseudoautosomal region and of the immediately adjacent part of the X specific region have also been analyzed. Two methods of linkage analysis were used: the affected sibling pair (ASP) method and the lod-score method. Lod-score analyses were performed on the basis of three different models--A, B, and C--all shown to be consistent with the epidemiological data on schizophrenia. No clear evidence for linkage was obtained with any of these models. However, whatever the genetic model and the disease classification, maximum lod scores were positive with most of the markers, with the highest scores generally being obtained for the DXYS14 locus. When the ASP method was used, the earlier finding of nonrandom segregation between schizophrenia and the DXYS14 locus was still supported in this larger data set, at an increased level of statistical significance. Findings of ASP analyses were not significant for the other loci. Thus, findings obtained from analyses using the ASP method, but not the lod-score method, were consistent with the pseudoautosomal hypothesis for schizophrenia.

Genetic pharmacotherapy as an early CNS drug development strategy: testing glutaminase inhibition for schizophrenia treatment in adult mice

Directory of Open Access Journals (Sweden)

Susana eMingote

2016-01-01

Full Text Available Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to test the therapeutic potential of glutaminase inhibition. We specifically asked whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG ERT2 cre/+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction — mimicking pharmacological inhibition — strongly

Group and site differences on the California Verbal Learning Test in persons with schizophrenia and their first-degree relatives: findings from the Consortium on the Genetics of Schizophrenia (COGS).

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Stone, William S; Giuliano, Anthony J; Tsuang, Ming T; Braff, David L; Cadenhead, Kristin S; Calkins, Monica E; Dobie, Dorcas J; Faraone, Stephen V; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Mintz, Jim; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Roe, Andrea H; Schork, Nicholas J; Siever, Larry J; Silverman, Jeremy M; Swerdlow, Neal R; Thomas, Alison R; Tsuang, Debby W; Turetsky, Bruce I; Seidman, Larry J

2011-05-01

Genetic studies of schizophrenia focus increasingly on putative endophenotypes because their genetic etiology may be simpler than clinical diagnosis. The Consortium on the Genetics of Schizophrenia (COGS), a multisite family study, aims to identify the genetic basis of several endophenotypes including verbal declarative memory (VDM), a neurocognitive function that shows robust impairment in schizophrenia. We present data on one type of measure of VDM, the California Verbal Learning Test, Second Edition (CVLT-II), in schizophrenia probands (n=305), their full biological siblings (n=449) and parents (n=232), and in community comparison subjects (CCS; n=509) across seven sites. Probands performed more poorly on each of five CVLT-II measures compared to related sibling and parent groups and CCS. Siblings and parents performed significantly worse than CCS on one measure (Discriminability), but with smaller effect sizes and less impairment than observed previously. The results raise questions about the homogeneity of VDM as an endophenotype, about methodological issues related to sampling, and about psychometric issues that impact the utility of the CVLT for detecting VDM deficits in nonpsychotic relatives of persons with schizophrenia. Copyright © 2011 Elsevier B.V. All rights reserved.

Early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition.

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Husted, Janice A; Ahmed, Rashid; Chow, Eva W C; Brzustowicz, Linda M; Bassett, Anne S

2012-05-01

There are few studies of environmental factors in familial forms of schizophrenia. We investigated whether childhood adversity or environmental factors were associated with schizophrenia in a familial sample where schizophrenia is associated with the NOSA1P gene. We found that a cumulative adversity index including childhood illness, family instability and cannabis use was significantly associated with narrow schizophrenia, independent of NOSA1P risk genotype, previously measured childhood trauma, covariates and familial clustering (adjusted odds ratio (95% confidence interval)=1.55 (1.01, 2.38)). The results provide further support that early environmental exposures influence schizophrenia expression even in the presence of strong genetic predisposition. Copyright © 2012 Elsevier B.V. All rights reserved.

Brain structure in people at ultra-high risk of psychosis, patients with first-episode schizophrenia, and healthy controls: a VBM study.

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Nenadic, Igor; Dietzek, Maren; Schönfeld, Nils; Lorenz, Carsten; Gussew, Alexander; Reichenbach, Jürgen R; Sauer, Heinrich; Gaser, Christian; Smesny, Stefan

2015-02-01

Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic-naïve first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetic association between the dopamine D1-receptor gene and paranoid schizophrenia in a northern Han Chinese population.

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Yao, Jun; Ding, Mei; Xing, Jiaxin; Xuan, Jinfeng; Pang, Hao; Pan, Yuqing; Wang, Baojie

2014-01-01

Dysregulation of dopaminergic neurotransmission at the D1 receptor in the prefrontal cortex has been implicated in the pathogenesis of schizophrenia. Genetic polymorphisms of the dopamine D1-receptor gene have a plausible role in modulating the risk of schizophrenia. To determine the role of DRD1 genetic polymorphisms as a risk factor for schizophrenia, we undertook a case-control study to look for an association between the DRD1 gene and schizophrenia. We genotyped eleven single-nucleotide polymorphisms within the DRD1 gene by deoxyribonucleic acid sequencing involving 173 paranoid schizophrenia patients and 213 unrelated healthy individuals. Statistical analysis was performed to identify the difference of genotype, allele, or haplotype distribution between cases and controls. A significantly lower risk of paranoid schizophrenia was associated with the AG + GG genotype of rs5326 and the AG + GG genotype of rs4532 compared to the AA genotype and the AA genotype, respectively. Distribution of haplotypes was no different between controls and paranoid schizophrenia patients. In the males, the genotype distribution of rs5326 was statistically different between cases and controls. In the females, the genotype distribution of rs4532 was statistically different between cases and controls. However, the aforementioned statistical significances were lost after Bonferroni correction. It is unlikely that DRD1 accounts for a substantial proportion of the genetic risk for schizophrenia. As an important dopaminergic gene, DRD1 may contribute to schizophrenia by interacting with other genes, and further relevant studies are warranted.

Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder

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Andreassen, O A; Harbo, H F; Wang, Y

2014-01-01

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotro...... and suggest that the MHC signals may differentiate SCZ from BD susceptibility.Molecular Psychiatry advance online publication, 28 January 2014; doi:10.1038/mp.2013.195....

The role of neurexins in schizophrenia and autistic spectrum disorder.

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Reichelt, A C; Rodgers, R J; Clapcote, S J

2012-03-01

Schizophrenia and autistic spectrum disorder (ASD) are common, chronic mental conditions with both genetic and environmental components to their aetiology. The identification of genes influencing susceptibility to these disorders offers a rational route towards a clearer understanding of the neurobiology, and with this the prospect of treatment and prevention strategies tailored towards the remediation of the altered pathways. Copy number variants (CNVs) underlie many serious illnesses, including neurological and neurodevelopmental syndromes. Recent studies assessing copy number variation in ASD and schizophrenia have repeatedly observed heterozygous deletions eliminating exons of the neurexin-1α gene (but not the neurexin-1β gene) in patients with ASD and schizophrenia. The neurexins are synaptic adhesion proteins that are known to play a key role in synaptic formation and maintenance. The functional significance of the recurrent deletion is poorly understood, but the availability of mice with deletion of the promoter and first exon of neurexin-1α provides direct access to the biological effects of neurexin-1α disruption on phenotypes relevant to ASD and schizophrenia. We review the evidence for the role of neurexin-1α in schizophrenia and ASD, and consider how genetic disruption of neurexin-1α may underpin the neuropathology contributing to these distinct neurodevelopmental disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges.

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O'Tuathaigh, Colm M P; Desbonnet, Lieve; Moran, Paula M; Kirby, Brian P; Waddington, John L

2011-01-01

Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.

The NCAN gene: schizophrenia susceptibility and cognitive dysfunction

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Wang P

2016-11-01

Full Text Available Peirong Wang,1 Jun Cai,2 Jianliang Ni,1 Jiangtao Zhang,1 Wei Tang,3 Chen Zhang2 1Department of Psychiatry, Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang, 2Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 3Wenzhou Kangning Hospital, Wenzhou, Zhejiang, People’s Republic of China Background: Cognitive dysfunction has been recognized as a cardinal feature of schizophrenia. Elucidating the neurobiological substrates of cognitive dysfunction in schizophrenia would help identify the underlying mechanism of this disorder. The rs1064395 single nucleotide polymorphism, within the gene encoding neurocan (NCAN, is reported to be associated with schizophrenia in European populations and may influence brain structure in patients with schizophrenia.Methods: In this study, we aimed to explore whether NCAN rs1064395 confers some risk for schizophrenia and cognitive dysfunction in Han Chinese. We recruited 681 patients with schizophrenia and 699 healthy subjects. Two hundred and fifty-four patients were evaluated according to Repeatable Battery for the Assessment of Neuropsychological Status (RBANS.Results: There were no significant differences in genotype or allele distributions of the rs1064395 polymorphism between the schizophrenia and control groups. Patients showed significantly poorer performance than controls on immediate memory, visuospatial skill, language, attention, delayed memory, and total RBANS score. Patients with the A/A or A/G genotype of rs1064395 had lower scores of immediate memory, visuospatial skill, attention, and total RBANS score than those with the G/G genotype. We performed an expression quantitative trait loci analysis and observed a significant association between rs1064395 and NCAN expression in the frontal (P=0.0022, P=0.022 after Bonferroni correction and cerebellar cortex (P=0.0032, P=0.032 after Bonferroni correction.Conclusion: Our findings indicate

Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs

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Lee, S Hong; DeCandia, Teresa R; Ripke, Stephan

2012-01-01

of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP...

A genetic deconstruction of neurocognitive traits in schizophrenia and bipolar disorder

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C.P.D. Fernandes (Carla P.); A. Christoforou (Andrea); S. Giddaluru (Sudheer); K.M. Ersland (Kari); S. Djurovic (Srdjan); M. Mattheisen (Manuel); A.J. Lundervold (Astri); I. Reinvang (Ivar); M.M. Nöthen (Markus); M. Rietschel (Marcella); R.A. Ophoff (Roel); A. Hofman (Albert); A.G. Uitterlinden (André); T.M. Werge (Thomas); S. Cichon (Sven); T. Espeseth (Thomas); O.A. Andreassen (Ole); V.M. Steen (Vidar); S. Le Hellard (Stephanie)

2013-01-01

textabstractBackground: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function

Additive genetic variation in schizophrenia risk is shared by populations of African and European descent

NARCIS (Netherlands)

De Candia, T.r.; Lee, S.H.; Yang, J.; Browning, B.L.; Gejman, P. V.; Levinson, D. F.; Mowry, B. J.; Hewitt, J.K.; Goddard, M.E.; O'Donovan, M.C.; Purcell, S.M.; Posthuma, D.; Visscher, P. M.; Wray, N.R.; Keller, M. C.

2013-01-01

To investigate the extent to which the proportion of schizophrenia's additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control

Sequential processing deficits in schizophrenia: relationship to neuropsychology and genetics.

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Hill, S Kristian; Bjorkquist, Olivia; Carrathers, Tarra; Roseberry, Jarett E; Hochberger, William C; Bishop, Jeffrey R

2013-12-01

Utilizing a combination of neuropsychological and cognitive neuroscience approaches may be essential for characterizing cognitive deficits in schizophrenia and eventually assessing cognitive outcomes. This study was designed to compare the stability of select exemplars for these approaches and their correlations in schizophrenia patients with stable treatment and clinical profiles. Reliability estimates for serial order processing were comparable to neuropsychological measures and indicate that experimental serial order processing measures may be less susceptible to practice effects than traditional neuropsychological measures. Correlations were moderate and consistent with a global cognitive factor. Exploratory analyses indicated a potentially critical role of the Met allele of the Catechol-O-methyltransferase (COMT) Val158Met polymorphism in externally paced sequential recall. Experimental measures of serial order processing may reflect frontostriatal dysfunction and be a useful supplement to large neuropsychological batteries. © 2013.

Prioritizing schizophrenia endophenotypes for future genetic studies: An example using data from the COGS-1 family study.

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Millard, Steven P; Shofer, Jane; Braff, David; Calkins, Monica; Cadenhead, Kristin; Freedman, Robert; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel; Gur, Ruben; Lazzeroni, Laura C; Light, Gregory A; Olincy, Ann; Nuechterlein, Keith; Seidman, Larry; Siever, Larry; Silverman, Jeremy; Stone, William S; Sprock, Joyce; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Ming; Turetsky, Bruce; Radant, Allen; Tsuang, Debby W

2016-07-01

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially. Published by Elsevier B.V.

A genetic deconstruction of neurocognitive traits in schizophrenia and bipolar disorder

DEFF Research Database (Denmark)

Fernandes, Carla P D; Christoforou, Andrea; Giddaluru, Sudheer

2013-01-01

Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals...

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

NARCIS (Netherlands)

Fernandes, Carla P. D.; Christoforou, Andrea; Giddaluru, Sudheer; Ersland, Kari M.; Djurovic, Srdjan; Mattheisen, Manuel; Lundervold, Astri J.; Reinvang, Ivar; Nöthen, Markus M.; Rietschel, Marcella; Ophoff, Roel A.; Hofman, Albert; Uitterlinden, André G.; Werge, Thomas; Cichon, Sven; Espeseth, Thomas; Andreassen, Ole A.; Steen, Vidar M.; Le Hellard, Stephanie; Kahn, René S.; Linszen, Don H.; van Os, Jim; Wiersma, Durk; Bruggeman, Richard; Cahn, Wiepke; de Haan, Lieuwe; Krabbendam, Lydia; Myin-Germeys, Inez

2013-01-01

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy

Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.

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Arne S Schaefer

2009-02-01

Full Text Available Recent studies indicate a mutual epidemiological relationship between coronary heart disease (CHD and periodontitis. Both diseases are associated with similar risk factors and are characterized by a chronic inflammatory process. In a candidate-gene association study, we identify an association of a genetic susceptibility locus shared by both diseases. We confirm the known association of two neighboring linkage disequilibrium regions on human chromosome 9p21.3 with CHD and show the additional strong association of these loci with the risk of aggressive periodontitis. For the lead SNP of the main associated linkage disequilibrium region, rs1333048, the odds ratio of the autosomal-recessive mode of inheritance is 1.99 (95% confidence interval 1.33-2.94; P = 6.9 x 10(-4 for generalized aggressive periodontitis, and 1.72 (1.06-2.76; P = 2.6 x 10(-2 for localized aggressive periodontitis. The two associated linkage disequilibrium regions map to the sequence of the large antisense noncoding RNA ANRIL, which partly overlaps regulatory and coding sequences of CDKN2A/CDKN2B. A closely located diabetes-associated variant was independent of the CHD and periodontitis risk haplotypes. Our study demonstrates that CHD and periodontitis are genetically related by at least one susceptibility locus, which is possibly involved in ANRIL activity and independent of diabetes associated risk variants within this region. Elucidation of the interplay of ANRIL transcript variants and their involvement in increased susceptibility to the interactive diseases CHD and periodontitis promises new insight into the underlying shared pathogenic mechanisms of these complex common diseases.

Computational Integration of Human Genetic Data to Evaluate AOP-Specific Susceptibility

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There is a need for approaches to efficiently evaluate human genetic variability and susceptibility related to environmental chemical exposure. Direct estimation of the genetic contribution to variability in susceptibility to environmental chemicals is only possible in special ca...

A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility.

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Carmona, F David; Mackie, Sarah L; Martín, Jose-Ezequiel; Taylor, John C; Vaglio, Augusto; Eyre, Stephen; Bossini-Castillo, Lara; Castañeda, Santos; Cid, Maria C; Hernández-Rodríguez, José; Prieto-González, Sergio; Solans, Roser; Ramentol-Sintas, Marc; González-Escribano, M Francisca; Ortiz-Fernández, Lourdes; Morado, Inmaculada C; Narváez, Javier; Miranda-Filloy, José A; Beretta, Lorenzo; Lunardi, Claudio; Cimmino, Marco A; Gianfreda, Davide; Santilli, Daniele; Ramirez, Giuseppe A; Soriano, Alessandra; Muratore, Francesco; Pazzola, Giulia; Addimanda, Olga; Wijmenga, Cisca; Witte, Torsten; Schirmer, Jan H; Moosig, Frank; Schönau, Verena; Franke, Andre; Palm, Øyvind; Molberg, Øyvind; Diamantopoulos, Andreas P; Carette, Simon; Cuthbertson, David; Forbess, Lindsy J; Hoffman, Gary S; Khalidi, Nader A; Koening, Curry L; Langford, Carol A; McAlear, Carol A; Moreland, Larry; Monach, Paul A; Pagnoux, Christian; Seo, Philip; Spiera, Robert; Sreih, Antoine G; Warrington, Kenneth J; Ytterberg, Steven R; Gregersen, Peter K; Pease, Colin T; Gough, Andrew; Green, Michael; Hordon, Lesley; Jarrett, Stephen; Watts, Richard; Levy, Sarah; Patel, Yusuf; Kamath, Sanjeet; Dasgupta, Bhaskar; Worthington, Jane; Koeleman, Bobby P C; de Bakker, Paul I W; Barrett, Jennifer H; Salvarani, Carlo; Merkel, Peter A; González-Gay, Miguel A; Morgan, Ann W; Martín, Javier

2015-04-02

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Consortium on the Genetics of Schizophrenia (COGS) assessment of endophenotypes for schizophrenia: an introduction to this Special Issue of Schizophrenia Research.

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Swerdlow, Neal R; Gur, Raquel E; Braff, David L

2015-04-01

The COGS is a multi-site NIMH-sponsored investigation of the genetic basis of 12 primary and multiple secondary quantitative endophenotypes in schizophrenia. Since 2003, COGS has completed studies using a family-based ascertainment strategy (COGS-1), and a case-control ascertainment strategy (COGS-2) (cumulative "n">4000). COGS-1 family study confirmed robust deficits in, and heritability of, these endophenotypes in schizophrenia, and provided evidence for a coherent genetic architecture underlying the risk for neurocognitive and neurophysiological deficits in this disorder. COGS-2 case-control findings, many reported herein, establish a foundation for fine genomic mapping and other analyses of these endophenotypes and risk genes for SZ. Several reports in this Special Issue compare findings of endophenotype deficits generated by fundamentally different COGS-1 vs. COGS-2 ascertainment strategies. Despite the expectation that family-based and case-control designs would establish demographically and potentially biologically distinct patient cohorts, findings generally revealed comparable patterns of endophenotype deficits across studies. The COGS-2 case-control design facilitated the accrual of a larger "n", permitting detailed analyses of factors moderating endophenotype performance. Some COGS-2 endophenotypes not assessed in COGS-1 are also reported, as is a new factor analytic strategy for identifying shared vs. unique factors among the COGS endophenotypes which can be used to develop composite variables with distinct genetic signatures. The path to date of COGS-1 endophenotype and genetic findings, followed by replication and extension in COGS-2, establishes benchmarks for endophenotype deficits in SZ and their moderation by specific factors, and clear expectations for informative findings from upcoming COGS-2 genetic analyses. Published by Elsevier B.V.

Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

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Lacko, Martin [Department of Otorhinolaryngology—Head and Neck Surgery, Maastricht University Medical Center, Maastricht (Netherlands); Braakhuis, Boudewijn J.M. [Department of Otolaryngology—Head and Neck Surgery, VU University Medical Center, Amsterdam (Netherlands); Sturgis, Erich M. [Department of Head and Neck Surgery and Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Boedeker, Carsten C. [Department of Otorhinolaryngology—Head and Neck Surgery, Albert-Ludwigs-University, Freiburg, Germany and Department of Otorhinolaryngology - Head and Neck Surgery, HELIOS Hanseklinikum Stralsund, Stralsund (Germany); Suárez, Carlos [Department of Otolaryngology, Hospital Universitario Central de Asturias, Oviedo (Spain); Instituto Universitario de Oncología del Principado de Asturias, Oviedo (Spain); Rinaldo, Alessandra; Ferlito, Alfio [ENT Clinic, University of Udine, Udine (Italy); Takes, Robert P., E-mail: robert.takes@radboudumc.nl [Department of Otolaryngology—Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen (Netherlands)

2014-05-01

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed.

Genetic Susceptibility to Head and Neck Squamous Cell Carcinoma

International Nuclear Information System (INIS)

Lacko, Martin; Braakhuis, Boudewijn J.M.; Sturgis, Erich M.; Boedeker, Carsten C.; Suárez, Carlos; Rinaldo, Alessandra; Ferlito, Alfio; Takes, Robert P.

2014-01-01

Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and its incidence is growing. Although environmental carcinogens and carcinogenic viruses are the main etiologic factors, genetic predisposition obviously plays a risk-modulating role, given that not all individuals exposed to these carcinogens experience the disease. This review highlights some aspects of genetic susceptibility to HNSCC: among others, genetic polymorphisms in biotransformation enzymes, DNA repair pathway, apoptotic pathway, human papillomavirus-related pathways, mitochondrial polymorphisms, and polymorphism related to the bilirubin-metabolized pathway. Furthermore, epigenetic variations, familial forms of HNSCC, functional assays for HNSCC risk assessment, and the implications and perspectives of research on genetic susceptibility in HNSCC are discussed

Metabotropic glutamate receptor 3 is associated with heroin dependence but not depression or schizophrenia in a Chinese population.

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Wei Jia

Full Text Available Metabotropic glutamate receptor subtype 3 (mGluR3, encoded by GRM3 plays important roles in the pathophysiology of schizophrenia, depression, and drug dependence. GRM3 polymorphisms were reported to be associated with prefrontal activity, cognitive shifting, and memory capability in healthy subjects, as well as susceptibility to schizophrenia and depression. The goal of this study was to replicate the association of GRM3 with schizophrenia and depression and to explore GRM3's potential association with heroin dependence (HD in a Chinese population. Seventeen SNPs throughout the GRM3 gene were genotyped using MALDI-TOF within the MassARRAY system, and the allele and genotype distributions were compared between 619 healthy controls and 433 patients with schizophrenia, 409 patients with major depression, and 584 unrelated addicts. We found that GRM3 polymorphisms modulate the susceptibility to HD but do not significantly influence the risk for schizophrenia or depression. An increased risk of HD was significantly associated with the minor alleles of two GRM3 SNPs, including the T allele of rs274618 (Odds ratio (OR = 1.631, 95% confidence interval (95%CI: 1.317-2.005, the T allele of rs274622 (OR = 1.652, 95% CI: 1.336-2.036, compared with the major alleles. The addicts carrying the minor allele of rs274618 or rs274622 had a shortened duration for transition from first use to dependence (DTFUD in comparison to homozygote for major allele (P<0.0001 for each SNP using log rank test. Additionally, a 6-SNP haplotype within 5' region of the GRM3 including the minor alleles of the two aforementioned SNPs was significantly associated with an increased risk of HD (P = 0.00001, OR = 1.668, 95% CI: 1.335-2.084. Our data indicated that GRM3 polymorphisms do not contribute to genetic susceptibility to schizophrenia and depression, but they confer an increased risk of HD in a Chinese population.

NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia

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Wen-Jun eGao

2013-03-01

Full Text Available Schizophrenia is a disabling mental illness that is now recognized as a neurodevelopmental disorder. It is likely that genetic risk factors interact with environmental perturbations to affect normal brain development and that this altered trajectory results in a combination of positive, negative, and cognitive symptoms. Although the exact pathophysiology of schizophrenia is unknown, the N-methyl-D-aspartate receptor (NMDAR, a major glutamate receptor subtype, has received great attention. Proper expression and regulation of NMDARs in the brain is critical for learning and memory processes as well as cortical plasticity and maturation. Evidence from both animal models and human studies implicates a dysfunction of NMDARs both in disease progression and symptoms of schizophrenia. Furthermore, mutations in many of the known genetic risk factors for schizophrenia suggest that NMDAR hypofunction is a convergence point for schizophrenia. In this review, we discuss how disrupted NMDAR function leads to altered neurodevelopment that may contribute to the progression and development of symptoms for schizophrenia, particularly cognitive deficits. We review the shared signaling pathways among the schizophrenia susceptibility genes DISC1, neuregulin1, and dysbindin, focusing on the AKT/GSK3β pathway, and how their mutations and interactions can lead to NMDAR dysfunction during development. Additionally, we explore what open questions remain and suggest where schizophrenia research needs to move in order to provide mechanistic insight into the cause of NMDAR dysfunction, as well as generate possible new avenues for therapeutic intervention.

Regional cerebral blood flow in schizophrenia

International Nuclear Information System (INIS)

Kanoh, Masayuki

1989-01-01

Regional cerebral blood flow (rCBF) was measured at rest using the 133 Xe inhalation technique in 40 DSM-III-diagnosed schizophrenics (22 males, 18 females: mean age 35.0 years, range 20-49 years) and 31 age-and sex-matched normal controls (16 males, 15 females: mean age 34.3 years, range 21-49 years). The absolute value (AV) and the percent value (PV) of the rCBF in schizophrenics were compared with those in controls. Correlations between rCBF and the Brief Psychiatric Rating Scale (BPRS) scores or the performance of Wisconsin Card Sorting Test (WCST) were examined in schizophrenics. Schizophrenics showed significantly lower AVs in all brain regions examined and a significantly lower PV in the left superior frontal region than controls. The hyperfrontal rCBF distribution which was found in both hemispheres in controls, was absent in the left hemisphere in schizophrenics. In schizophrenics, superior frontal blood flows were significantly negatively correlated with the negative symptom scores of the BPRS but not with the total scores and the positive symptom scores of the BPRS. In schizophrenics, inferior frontal blood flows were significantly correlated with the number of sorting categories achieved. These results indicate that rCBF in schizophrenia is reduced in the whole brain and especially in the left superior frontal region. These findings suggest a frontal lobe dysfunction in schizophrenia. (author)

The Role of Catechol-O-Methyltransferase (COMT Gene in the Etiopathogenesis of Schizophrenia

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Ceren Acar

2014-09-01

Full Text Available Genetic factors in the risk of developing schizophrenia is of great importance. With the help of the advances in the field of genetics in recent years by using linkage analysis several genes have been identified that may be a risk factor in schizophrenia. Several association studies have been performed in many different populations on the candidate susceptibility genes that were defined in previous studies. However, these studies give controversial results in different countries with different populations, and there are problems in obtaining replicable results. In this review we aimed to focus on the genetic basis of schizophrenia and the relationship between schizophrenia and catechol-O-methyltransferase (COMT gene. COMT encodes an enzyme molecule which has an important function in dopamine pathways. It has great importance in catecholamine metabolism and pharmacology and genetic mechanism of catechol metabolism variations and their clinical consequences. COMT transfers the methyl group from S-adenosyl-methionine to the hydroxyl group of catechol nucleus (such as dopamine, norepinephrine or catechol estrogen. Genetic variations found in COMT gene are associated with a broad spectrum of clinical phenotype including psychiatric disorders or estrogen related cancers. Several groups have performed studies on the relationship between schizophrenia and COMT. The most commonly studied polymorphism in COMT gene is rs4680 and it causes a valine methionine conversion at codon 158. The association studies on this polymorphism in different populations gave both positive and negative results. Schizoprenia is a complex disease caused by the interaction of environmental and genetic factors, while interpreting the genetic data, this fact and the possibility of the presence of different gene products should be taken into account. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(3.000: 217-226

Immunogenetics and genetic susceptibility in the pathogenesis of autoimmune hepatitis

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Das Anup K

2014-11-01

Full Text Available vAutoimmune hepatitis is a progressive liver disease. Its pathogenesis is unclear, but needs a ‘trigger’ to initiate the disease in a genetically susceptible person. The susceptibility is partly related to MHCII class genes, and more so with human leukocyte antigen (HLA. Several mechanisms have been proposed which, however, cannot fully explain the immunologic findings in autoimmune hepatitis. The susceptibility to any autoimmune disease is determined by several factors where genetic and immunological alterations, along with, environmental factor are active. MHCII antigens as a marker for AIH, or a predictor of treatment response and prognosis has been investigated. Since MHCII antigens show significant ethnic heterogeneity, mutations in MHCII may merely act as only precursors of the surface markers of immune cells, which can be of significance, because the changes in HLA and MHC are missing in certain populations. One such marker is the CTLA-4 (CD152 gene mutation, reported in the phenotypes representing susceptibility to AIH. Other candidate genes of cytokines, TNF, TGF-beta1 etc, have also been investigated but with unvalidated results. Paediatric AIH show differences in genetic susceptibility. Genetic susceptibility or resistance to AIH may be associated with polypeptides in DRB1 with certain amino-acid sequences. Understanding which genes are implicated in genesis and/or disease progression will obviously help to identify key pathways in AIH and provide better insights into its pathogenesis. But studies to identify responsible genes are complex because of the complex trait of AIH.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

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Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S

2018-01-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns...... the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes...... in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely...

Population genetic testing for cancer susceptibility: founder mutations to genomes.

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Foulkes, William D; Knoppers, Bartha Maria; Turnbull, Clare

2016-01-01

The current standard model for identifying carriers of high-risk mutations in cancer-susceptibility genes (CSGs) generally involves a process that is not amenable to population-based testing: access to genetic tests is typically regulated by health-care providers on the basis of a labour-intensive assessment of an individual's personal and family history of cancer, with face-to-face genetic counselling performed before mutation testing. Several studies have shown that application of these selection criteria results in a substantial proportion of mutation carriers being missed. Population-based genetic testing has been proposed as an alternative approach to determining cancer susceptibility, and aims for a more-comprehensive detection of mutation carriers. Herein, we review the existing data on population-based genetic testing, and consider some of the barriers, pitfalls, and challenges related to the possible expansion of this approach. We consider mechanisms by which population-based genetic testing for cancer susceptibility could be delivered, and suggest how such genetic testing might be integrated into existing and emerging health-care structures. The existing models of genetic testing (including issues relating to informed consent) will very likely require considerable alteration if the potential benefits of population-based genetic testing are to be fully realized.

Transcription factor SP4 is a susceptibility gene for bipolar disorder.

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Xianjin Zhou

Full Text Available The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018. To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029, and two of them (rs12673091, rs3735440 were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012 also displayed a significant association. The SNP7 (rs12673091 was therefore significantly associated in all three samples, and shared the same susceptibility allele (A across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these

Regional cerebral blood flow in schizophrenia

International Nuclear Information System (INIS)

Mathew, R.J.; Duncan, G.C.; Weinman, M.L.; Barr, D.L.

1982-01-01

Regional cerebral blood flow (rCBF) was measured via xenon133 inhalation technique in 23 patients with schizophrenia and 18 age- and sex-matched controls. The mean blood flow to both hemispheres was found to be lower for the patients. The patients and their controls did not differ on interhemispheric differences in blood flow. There were no differences in rCBF between medicated and unmedicated, subchronic and chronic, and paranoid and nonparanoid patients. Hallucinations were associated with reduced blood flow to several postcentral regions

Regional cerebral blood flow in schizophrenia

Energy Technology Data Exchange (ETDEWEB)

Mathew, R.J.; Duncan, G.C.; Weinman, M.L.; Barr, D.L.

1982-10-01

Regional cerebral blood flow (rCBF) was measured via xenon133 inhalation technique in 23 patients with schizophrenia and 18 age- and sex-matched controls. The mean blood flow to both hemispheres was found to be lower for the patients. The patients and their controls did not differ on interhemispheric differences in blood flow. There were no differences in rCBF between medicated and unmedicated, subchronic and chronic, and paranoid and nonparanoid patients. Hallucinations were associated with reduced blood flow to several postcentral regions.

Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases

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Pouget, Jennie G; Gonçalves, Vanessa F; Spain, Sarah L

2016-01-01

There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies. The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been...... in immune genes contributes to schizophrenia. We show that there is no enrichment of immune loci outside of the MHC region in the largest genetic study of schizophrenia conducted to date, in contrast to 5 diseases of known immune origin. Among 108 regions of the genome previously associated...

Exploration of genetic susceptibility factors for Parkinson's disease

Indian Academy of Sciences (India)

Home; Journals; Journal of Genetics; Volume 89; Issue 2. Exploration of genetic susceptibility factors for Parkinson's disease in a South American sample. Bruno A. Benitez Diego A. Forero Gonzalo H. Arboleda Luis A. Granados Juan J. Yunis William Fernandez Humberto Arboleda. Research Note Volume 89 Issue 2 ...

Regionally specific white matter disruptions of fornix and cingulum in schizophrenia.

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Muhammad Farid Abdul-Rahman

Full Text Available Limbic circuitry disruptions have been implicated in the psychopathology and cognitive deficits of schizophrenia, which may involve white matter disruptions of the major tracts of the limbic system, including the fornix and the cingulum. Our study aimed to investigate regionally specific abnormalities of the fornix and cingulum in schizophrenia using diffusion tensor imaging (DTI. We determined the fractional anisotropy (FA, radial diffusivity (RD, and axial diffusivity (AD profiles along the fornix and cingulum tracts using a fibertracking technique and a brain mapping algorithm, the large deformation diffeomorphic metric mapping (LDDMM, in the DTI scans of 33 patients with schizophrenia and 31 age-, gender-, and handedness-matched healthy controls. We found that patients with schizophrenia showed reduction in FA and increase in RD in bilateral fornix, and increase in RD in left anterior cingulum when compared to healthy controls. In addition, tract-based analysis revealed specific loci of these white matter differences in schizophrenia, that is, FA reductions and AD and RD increases occur in the region of the left fornix further from the hippocampus, FA reductions and RD increases occur in the rostral portion of the left anterior cingulum, and RD and AD increases occur in the anterior segment of the left middle cingulum. In patients with schizophrenia, decreased FA in the specific loci of the left fornix and increased AD in the right cingulum adjoining the hippocampus correlated with greater severity of psychotic symptoms. These findings support precise disruptions of limbic-cortical integrity in schizophrenia and disruption of these structural networks may contribute towards the neural basis underlying the syndrome of schizophrenia and clinical symptomatology.

Attention/vigilance in schizophrenia: performance results from a large multi-site study of the Consortium on the Genetics of Schizophrenia (COGS).

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Nuechterlein, Keith H; Green, Michael F; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2015-04-01

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity. Copyright © 2015 Elsevier B.V. All rights reserved.

Genetic analysis for two italian siblings with usher syndrome and schizophrenia.

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Domanico, Daniela; Fragiotta, Serena; Trabucco, Paolo; Nebbioso, Marcella; Vingolo, Enzo Maria

2012-01-01

Usher syndrome is a group of autosomal recessive genetic disorders characterized by deafness, retinitis pigmentosa, and sometimes vestibular areflexia. The relationship between Usher syndrome and mental disorders, most commonly a "schizophrenia-like" psychosis, is sometimes described in the literature. The etiology of psychiatric expression of Usher syndrome is still unclear. We reported a case of two natural siblings with congenital hypoacusis, retinitis pigmentosa, and psychiatric symptoms. Clinical features and genetic analysis were also reported. We analyzed possible causes to explain the high prevalence of psychiatric manifestations in Usher syndrome: genetic factors, brain damage, and "stress-related" hypothesis.

Genetic Analysis for Two Italian Siblings with Usher Syndrome and Schizophrenia

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Daniela Domanico

2012-01-01

Full Text Available Usher syndrome is a group of autosomal recessive genetic disorders characterized by deafness, retinitis pigmentosa, and sometimes vestibular areflexia. The relationship between Usher syndrome and mental disorders, most commonly a “schizophrenia-like” psychosis, is sometimes described in the literature. The etiology of psychiatric expression of Usher syndrome is still unclear. We reported a case of two natural siblings with congenital hypoacusis, retinitis pigmentosa, and psychiatric symptoms. Clinical features and genetic analysis were also reported. We analyzed possible causes to explain the high prevalence of psychiatric manifestations in Usher syndrome: genetic factors, brain damage, and “stress-related” hypothesis.

Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population.

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Ming Li

Full Text Available Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N = 12, including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p = 0.10, odds ratio = 1.06, 95% confidence interval = 0.99-1.13. Such absence of association was further confirmed by the non-superiority test (p = 0.0003, suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations.

Vitamin D insufficiency and schizophrenia risk: evaluation of hyperprolinemia as a mediator of association.

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Clelland, James D; Read, Laura L; Drouet, Valérie; Kaon, Angela; Kelly, Alexandra; Duff, Karen E; Nadrich, Robert H; Rajparia, Amit; Clelland, Catherine L

2014-06-01

25-Hydroxyvitamin D (25(OH)D) deficits have been associated with schizophrenia susceptibility and supplementation has been recommended for those at-risk. Although the mechanism by which a deficit confers risk is unknown, vitamin D is a potent transcriptional modulator and can regulate proline dehydrogenase (PRODH) expression. PRODH maps to chromosome 22q11, a region conferring the highest known genetic risk of schizophrenia, and encodes proline oxidase, which catalyzes proline catabolism. l-Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with decreased IQ, cognitive impairment, schizoaffective disorder, and schizophrenia. We investigated the relationship between 25(OH)D and schizophrenia, comparing fasting plasma 25(OH)D in 64 patients and 90 matched controls. We then tested for a mediating effect of hyperprolinemia on the association between 25(OH)D and schizophrenia. 25(OH)D levels were significantly lower in patients, and 25(OH)D insufficiency associated with schizophrenia (OR 2.1, adjusted p=0.044, 95% CI: 1.02-4.46). Moreover, 25(OH)D insufficient subjects had three times greater odds of hyperprolinemia than those with optimal levels (p=0.035, 95% CI: 1.08-8.91), and formal testing established that hyperprolinemia is a significantly mediating phenotype that may explain over a third of the effect of 25(OH)D insufficiency on schizophrenia risk. This study presents a mechanism by which 25(OH)D insufficiency confers risk of schizophrenia; via proline elevation due to reduced PRODH expression, and a concomitant dysregulation of neurotransmission. Although definitive causality cannot be confirmed, these findings strongly support vitamin D supplementation in patients, particularly for those with elevated proline, who may represent a large subgroup of the schizophrenia population. Copyright © 2014 Elsevier B.V. All rights reserved.

The phenotypic manifestations of rare CNVs in schizophrenia.

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Merikangas, Alison K; Segurado, Ricardo; Cormican, Paul; Heron, Elizabeth A; Anney, Richard J L; Moore, Susan; Kelleher, Eric; Hargreaves, April; Anderson-Schmidt, Heike; Gill, Michael; Gallagher, Louise; Corvin, Aiden

2014-09-01

There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function. Copyright © 2014 Elsevier B.V. All rights reserved.

The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis

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Saetre, Peter; Lundmark, Per; Wang, August

2010-01-01

Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been...... associated with schizophrenia. The minor allele (A) of this polymorphism (A218C) is also more frequent in patients who have attempted suicide and individuals who died by suicide, than in healthy control individuals. In an attempt to replicate previous findings, five single nucleotide polymorphisms (SNPs......) were genotyped in 837 Scandinavian schizophrenia patients and 1,473 controls. Three SNPs spanning intron 6 and 7, including the A218C and A779C polymorphisms, were associated with schizophrenia susceptibility (P = 0.019). However there were no differences in allele frequencies of these loci between...

Loss of Function Studies in Mice and Genetic Association Link Receptor Protein Tyrosine Phosphatase a to Schizophrenia

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Takahashi, Nagahide; Nielsen, Karin Sandager; Aleksic, Branko

2011-01-01

Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPa, in the control of radial neuronal migration, cortical cytoarchitecture...

Age of Onset in Schizophrenia Spectrum Disorders: Complex Interactions between Genetic and Environmental Factors.

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Mandelli, Laura; Toscano, Elena; Porcelli, Stefano; Fabbri, Chiara; Serretti, Alessandro

2016-03-01

In this study we evaluated the role of a candidate gene for major psychosis, Sialyltransferase (ST8SIA2), in the risk to develop a schizophrenia spectrum disorders, taking into account exposure to stressful life events (SLEs). Eight polymorphisms (SNPs) were tested in 94 Schizophreniainpatients and 176 healthy controls. Schizophrenia patients were also evaluated for SLEs in different life periods. None of the SNPs showed association with schizophrenia. Nevertheless, when crossing genetic variants with childhood SLEs, we could observe trends of interaction with age of onset. Though several limitations, our results support a protective role of ST8SIA2 in individuals exposed to moderate childhood stress.

Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region

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Stewart, Paula; Campbell, Lauren; Skogtvedt, Susan; Griffin, Karen A.; Arnemo, Jon M.; Tryland, Morten; Girling, Simon; Miller, Michael W.; Tranulis, Michael A.; Goldmann, Wilfred

2012-01-01

Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE) during the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD) remains an open question. Variation in the host-encoded prion protein (PrPC) largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrPC protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo) and pine marten (Martes martes) were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus) and mountain lion (Puma concolor) from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter. PMID:23236380

Genetic predictions of prion disease susceptibility in carnivore species based on variability of the prion gene coding region.

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Paula Stewart

Full Text Available Mammalian species vary widely in their apparent susceptibility to prion diseases. For example, several felid species developed prion disease (feline spongiform encephalopathy or FSE during the bovine spongiform encephalopathy (BSE epidemic in the United Kingdom, whereas no canine BSE cases were detected. Whether either of these or other groups of carnivore species can contract other prion diseases (e.g. chronic wasting disease or CWD remains an open question. Variation in the host-encoded prion protein (PrP(C largely explains observed disease susceptibility patterns within ruminant species, and may explain interspecies differences in susceptibility as well. We sequenced and compared the open reading frame of the PRNP gene encoding PrP(C protein from 609 animal samples comprising 29 species from 22 genera of the Order Carnivora; amongst these samples were 15 FSE cases. Our analysis revealed that FSE cases did not encode an identifiable disease-associated PrP polymorphism. However, all canid PrPs contained aspartic acid or glutamic acid at codon 163 which we propose provides a genetic basis for observed susceptibility differences between canids and felids. Among other carnivores studied, wolverine (Gulo gulo and pine marten (Martes martes were the only non-canid species to also express PrP-Asp163, which may impact on their prion diseases susceptibility. Populations of black bear (Ursus americanus and mountain lion (Puma concolor from Colorado showed little genetic variation in the PrP protein and no variants likely to be highly resistant to prions in general, suggesting that strain differences between BSE and CWD prions also may contribute to the limited apparent host range of the latter.

Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia.

Science.gov (United States)

Cosgrove, Victoria E; Suppes, Trisha

2013-05-14

The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate. Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research. For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis.

Genetic modelling in schizophrenia according to HLA typing.

Science.gov (United States)

Smeraldi, E; Macciardi, F; Gasperini, M; Orsini, A; Bellodi, L; Fabio, G; Morabito, A

1986-09-01

Studying families of schizophrenic patients, we observed that the risk of developing the overt form of the illness could be enhanced by some factors. Among these various factors we focused our attention on a biological variable, namely the presence or the absence of particular HLA antigens: partitioning our schizophrenic patients according to their HLA structure (i.e. those with HLA-A1 or CRAG-A1 antigens and those with HLA-non-CRAG-A1 antigens, respectively), revealed different illness distribution in the two groups. From a genetic point of view, this finding suggests the presence of heterogeneity in the hypothetical liability system related to schizophrenia and we evaluated the heterogeneity hypothesis by applying alternative genetic models to our data, trying to detect more biologically homogeneous subgroups of the disease.

Possible association between interleukin-1β gene and schizophrenia in a Japanese population.

Science.gov (United States)

Sasayama, Daimei; Hori, Hiroaki; Teraishi, Toshiya; Hattori, Kotaro; Ota, Miho; Iijima, Yoshimi; Tatsumi, Masahiko; Higuchi, Teruhiko; Amano, Naoji; Kunugi, Hiroshi

2011-08-16

Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1β) in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years) and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years) were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were examined for association with schizophrenia. Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089). When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073). A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032). The present study shows the first evidence that the IL-1β gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1β gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1β in the etiology of schizophrenia.

Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

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Sasayama Daimei

2011-08-01

Full Text Available Abstract Background Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1β in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. Methods A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944 were examined for association with schizophrenia. Results Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089. When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073. A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032. Conclusions The present study shows the first evidence that the IL-1β gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1β gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1β in the etiology of schizophrenia.

Possible association between Interleukin-1beta gene and schizophrenia in a Japanese population

Science.gov (United States)

2011-01-01

Background Several lines of evidence have implicated the pro-inflammatory cytokine interleukin-1beta (IL-1β) in the etiology of schizophrenia. Although a number of genetic association studies have been reported, very few have systematically examined gene-wide tagging polymorphisms. Methods A total of 533 patients with schizophrenia (302 males: mean age ± standard deviation 43.4 ± 13.0 years; 233 females; mean age 44.8 ± 15.3 years) and 1136 healthy controls (388 males: mean age 44.6 ± 17.3 years; 748 females; 46.3 ± 15.6 years) were recruited for this study. All subjects were biologically unrelated Japanese individuals. Five tagging polymorphisms of IL-1β gene (rs2853550, rs1143634, rs1143633, rs1143630, rs16944) were examined for association with schizophrenia. Results Significant difference in allele distribution was found between patients with schizophrenia and controls for rs1143633 (P = 0.0089). When the analysis was performed separately in each gender, significant difference between patients and controls in allele distribution of rs1143633 was observed in females (P = 0.0073). A trend towards association was also found between rs16944 and female patients with schizophrenia (P = 0.032). Conclusions The present study shows the first evidence that the IL-1β gene polymorphism rs1143633 is associated with schizophrenia susceptibility in a Japanese population. The results suggest the possibility that the influence of IL-1β gene variations on susceptibility to schizophrenia may be greater in females than in males. Findings of the present study provide further support for the role of IL-1β in the etiology of schizophrenia. PMID:21843369

Genetic Testing for TMEM154 Mutations Associated with Lentivirus Susceptibility in Sheep

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Petrik, Dustin T.; Simpson, Barry; Kijas, James W.; Clawson, Michael L.; Chitko-McKown, Carol G.; Harhay, Gregory P.; Leymaster, Kreg A.

2013-01-01

In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV) in the U.S., and Visna/Maedi virus (VMV) elsewhere, these viruses reduce an animal’s health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154) has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E) at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V) and the extracellular domains (E31Q, I74F, and I102T) of TMEM154. A matrix-assisted laser desorption/ionization–time-of flight mass spectrometry (MALDI-TOF MS) assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes). The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks. PMID:23408992

Genetic testing for TMEM154 mutations associated with lentivirus susceptibility in sheep.

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Michael P Heaton

Full Text Available In sheep, small ruminant lentiviruses cause an incurable, progressive, lymphoproliferative disease that affects millions of animals worldwide. Known as ovine progressive pneumonia virus (OPPV in the U.S., and Visna/Maedi virus (VMV elsewhere, these viruses reduce an animal's health, productivity, and lifespan. Genetic variation in the ovine transmembrane protein 154 gene (TMEM154 has been previously associated with OPPV infection in U.S. sheep. Sheep with the ancestral TMEM154 haplotype encoding glutamate (E at position 35, and either form of an N70I variant, were highly-susceptible compared to sheep homozygous for the K35 missense mutation. Our current overall aim was to characterize TMEM154 in sheep from around the world to develop an efficient genetic test for reduced susceptibility. The average frequency of TMEM154 E35 among 74 breeds was 0.51 and indicated that highly-susceptible alleles were present in most breeds around the world. Analysis of whole genome sequences from an international panel of 75 sheep revealed more than 1,300 previously unreported polymorphisms in a 62 kb region containing TMEM154 and confirmed that the most susceptible haplotypes were distributed worldwide. Novel missense mutations were discovered in the signal peptide (A13V and the extracellular domains (E31Q, I74F, and I102T of TMEM154. A matrix-assisted laser desorption/ionization-time-of flight mass spectrometry (MALDI-TOF MS assay was developed to detect these and six previously reported missense and two deletion mutations in TMEM154. In blinded trials, the call rate for the eight most common coding polymorphisms was 99.4% for 499 sheep tested and 96.0% of the animals were assigned paired TMEM154 haplotypes (i.e., diplotypes. The widespread distribution of highly-susceptible TMEM154 alleles suggests that genetic testing and selection may improve the health and productivity of infected flocks.

Computational Integration of Human Genetic and Toxicological Data to Evaluate AOP-Specific Susceptibility

Science.gov (United States)

Susceptibility to environmental chemicals can be modulated by genetic differences. Direct estimation of the genetic contribution to variability in susceptibility to environmental chemicals is only possible in special cases where there is an observed association between exposure a...

Methylenetetrahydrofolate reductase A1298C genetic variant& risk of schizophrenia: A meta-analysis.

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Rai, Vandana; Yadav, Upendra; Kumar, Pradeep; Yadav, Sushil K; Gupta, Sanjay

2017-04-01

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate metabolism, whose role in schizophrenia is debatable. Numerous case-control studies have investigated the association of MTHFR A1298C polymorphism with schizophrenia, but results are controversial. The aim of the present study was to find the association between MTHFR A1298C gene polymorphism and schizophrenia. PubMed, Google Scholar, Science Direct and Springer link databases were searched for case-control association studies in which MTHFR A1298C polymorphism was investigated as a risk factor for schizophrenia. In all, 19 studies with 4049 cases and 5488 controls were included in this meta-analysis. Odds ratios (ORs) with 95 per cent confidence intervals (CIs) were used as an association measure. The results of meta-analysis reported a significant association between A1298C polymorphism and schizophrenia risk in overall comparisons in all genetic models (C vs. A: OR=1.13, 95% CI=1.01-1.27, P=0.02; CC vs. AA: OR=1.20, 95% CI=1.03-1.39, P=0.02; AC vs. AA: OR=1.13, 95% CI=1.03-1.23, P=0.009; AC+CC vs. AA: OR=1.14, 95% CI=1.02-1.24, P=0.002; CC vs. AA+AC: OR=1.17, 95% CI=1.01-1.35, P=0.04). MTHFR A1298C polymorphism was found to be a risk factor for schizophrenia and might have played a significant role in the pathogenesis of schizophrenia.

Genetic architecture of intrinsic antibiotic susceptibility.

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Hany S Girgis

2009-05-01

Full Text Available Antibiotic exposure rapidly selects for more resistant bacterial strains, and both a drug's chemical structure and a bacterium's cellular network affect the types of mutations acquired.To better characterize the genetic determinants of antibiotic susceptibility, we exposed a transposon-mutagenized library of Escherichia coli to each of 17 antibiotics that encompass a wide range of drug classes and mechanisms of action. Propagating the library for multiple generations with drug concentrations that moderately inhibited the growth of the isogenic parental strain caused the abundance of strains with even minor fitness advantages or disadvantages to change measurably and reproducibly. Using a microarray-based genetic footprinting strategy, we then determined the quantitative contribution of each gene to E. coli's intrinsic antibiotic susceptibility. We found both loci whose removal increased general antibiotic tolerance as well as pathways whose down-regulation increased tolerance to specific drugs and drug classes. The beneficial mutations identified span multiple pathways, and we identified pairs of mutations that individually provide only minor decreases in antibiotic susceptibility but that combine to provide higher tolerance.Our results illustrate that a wide-range of mutations can modulate the activity of many cellular resistance processes and demonstrate that E. coli has a large mutational target size for increasing antibiotic tolerance. Furthermore, the work suggests that clinical levels of antibiotic resistance might develop through the sequential accumulation of chromosomal mutations of small individual effect.

Genetic variation of the riparian pioneer tree species populus nigra. II. Variation In susceptibility to the foliar rust melampsora larici-populina

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Legionnet; Muranty; Lefevre

1999-04-01

Partial resistance of Populus nigra L. to three races of the foliar rust Melampsora larici-populina Kleb. was studied in a field trial and in laboratory tests, using a collection of P. nigra originating from different places throughout France. No total resistance was found. The partial resistance was split into epidemiological components, which proved to be under genetic control. Various patterns of association of epidemiological components values were found. Principal components analysis revealed their relationships. Only 24% of the variance of the field susceptibility could be explained by the variation of the epidemiological components of susceptibility. This variable was significantly correlated with susceptibility to the most ancient and widespread race of the pathogen, and with the variables related to the size of the lesions of the different races. Analysis of variance showed significant differences in susceptibility between regions and between stands within one region. Up to 20% of variation was between regions, and up to 22% between stands, so that these genetic factors appeared to be more differentiated than the neutral diversity (up to 3.5% Legionnet & Lefevre, 1996). However, no clear pattern of geographical distribution of diversity was detected.

Integrated Pathway-Based Approach Identifies Association between Genomic Regions at CTCF and CACNB2 and Schizophrenia

NARCIS (Netherlands)

Juraeva, Dilafruz; Haenisch, Britta; Zapatka, Marc; Frank, Josef; Witt, Stephanie H.; Mühleisen, Thomas W.; Treutlein, Jens; Strohmaier, Jana; Meier, Sandra; Degenhardt, Franziska; Giegling, Ina; Ripke, Stephan; Leber, Markus; Lange, Christoph; Schulze, Thomas G.; Mössner, Rainald; Nenadic, Igor; Sauer, Heinrich; Rujescu, Dan; Maier, Wolfgang; Børglum, Anders; Ophoff, Roel; Cichon, Sven; Nöthen, Markus M.; Rietschel, Marcella; Mattheisen, Manuel; Brors, Benedikt; Kahn, René S.; Cahn, Wiepke; Linszen, Don H.; de Haan, Lieuwe; van Os, Jim; Krabbendam, Lydia; Myin-Germeys, Inez; Wiersma, Durk; Bruggeman, Richard; Mors, O.; Børglum, A. D.; Mortensen, P. B.; Pedersen, C. B.; Demontis, D.; Grove, J.; Mattheisen, M.; Hougaard, D. M.

2014-01-01

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional

The tryptophan hydroxylase 1 (TPH1) gene, schizophrenia susceptibility, and suicidal behavior: a multi-centre case-control study and meta-analysis

DEFF Research Database (Denmark)

Saetre, Peter; Lundmark, Per; Wang, August

2010-01-01

Serotonin (5-hydroxytryptamin; 5-HT) alternations has since long been suspected in the pathophysiology of schizophrenia. Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH) is the rate-limiting enzyme in the biosynthesis of 5-HT, and sequence variation in intron 6 of the TPH1 gene has been...... affected individuals having attempted suicide at least once and patients with no history of suicide attempts (P = 0.84). A systematic literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17, 95% confidence interval 1.......07-1.29). Association studies on suicide attempts are however conflicting (heterogeneity index I(2) = 0.54) and do not support the A218C/A779C polymorphisms being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR = 0.96 [0.80-1.16]). We conclude that the TPH1 A218...

Risk-Conferring Glutamatergic Genes and Brain Glutamate Plus Glutamine in Schizophrenia

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Juan R. Bustillo

2017-06-01

Full Text Available BackgroundThe proton magnetic resonance spectroscopy (1H-MRS signals from glutamate (or the combined glutamate and glutamine signal—Glx have been found to be greater in various brain regions in people with schizophrenia. Recently, the Psychiatric Genetics Consortium reported that several common single-nucleotide polymorphisms (SNPs in glutamate-related genes confer increased risk of schizophrenia. Here, we examined the relationship between presence of these risk polymorphisms and brain Glx levels in schizophrenia.Methods1H-MRS imaging data from an axial, supraventricular tissue slab were acquired in 56 schizophrenia patients and 67 healthy subjects. Glx was measured in gray matter (GM and white matter (WM regions. The genetic data included six polymorphisms genotyped across an Illumina 5M SNP array. Only three of six glutamate as well as calcium-related SNPs were available for examination. These included three glutamate-related polymorphisms (rs10520163 in CLCN3, rs12704290 in GRM3, and rs12325245 in SLC38A7, and three calcium signaling polymorphisms (rs1339227 in RIMS1, rs7893279 in CACNB2, and rs2007044 in CACNA1C. Summary risk scores for the three glutamate and the three calcium polymorphisms were calculated.ResultsGlx levels in GM positively correlated with glutamate-related genetic risk score but only in younger (≤36 years schizophrenia patients (p = 0.01. Glx levels did not correlate with calcium risk scores. Glx was higher in the schizophrenia group compared to levels in controls in GM and WM regardless of age (p < 0.001.ConclusionElevations in brain Glx are in part, related to common allelic variants of glutamate-related genes known to increase the risk for schizophrenia. Since the glutamate risk scores did not differ between groups, some other genetic or environmental factors likely interact with the variability in glutamate-related risk SNPs to contribute to an increase in brain Glx early in the illness.

Regional cerebral blood flow distribution in newly diagnosed schizophrenia and schizophreniform disorder

DEFF Research Database (Denmark)

Rubin, P; Holm, S; Madsen, P L

1994-01-01

Regional cerebral blood flow distribution (rCBF) in 24 first admissions with schizophrenia or schizophreniform disorder and in 17 healthy volunteers was examined. Single photon emission computed tomography with a brain-retained tracer, technetium-99m-d,l-hexamethyl-propylene amine oxime, was used...... interrelationship in schizophrenia and schizophreniform disorder....

Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis.

Science.gov (United States)

Shibuya, Masako; Watanabe, Yuichiro; Nunokawa, Ayako; Egawa, Jun; Kaneko, Naoshi; Igeta, Hirofumi; Someya, Toshiyuki

2014-01-01

Interleukin-1 beta (IL-1β) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis. We tested the association between IL1B and schizophrenia in 1229 case-control and 112 trio samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 trio samples from 16 independent populations. We found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or trio samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia. The present study does not support a role for IL1B in schizophrenia susceptibility.

Comprehensive association analysis of 27 genes from the GABAergic system in Japanese individuals affected with schizophrenia.

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Balan, Shabeesh; Yamada, Kazuo; Iwayama, Yoshimi; Hashimoto, Takanori; Toyota, Tomoko; Shimamoto, Chie; Maekawa, Motoko; Takagai, Shu; Wakuda, Tomoyasu; Kameno, Yosuke; Kurita, Daisuke; Yamada, Kohei; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Yoshikawa, Takeo

2017-07-01

Involvement of the gamma-aminobutyric acid (GABA)-ergic system in schizophrenia pathogenesis through disrupted neurodevelopment has been highlighted in numerous studies. However, the function of common genetic variants of this system in determining schizophrenia risk is unknown. We therefore tested the association of 375 tagged SNPs in genes derived from the GABAergic system, such as GABA A receptor subunit genes, and GABA related genes (glutamate decarboxylase genes, GABAergic-marker gene, genes involved in GABA receptor trafficking and scaffolding) in Japanese schizophrenia case-control samples (n=2926; 1415 cases and 1511 controls). We observed nominal association of SNPs in nine GABA A receptor subunit genes and the GPHN gene with schizophrenia, although none survived correction for study-wide multiple testing. Two SNPs located in the GABRA1 gene, rs4263535 (P allele =0.002; uncorrected) and rs1157122 (P allele =0.006; uncorrected) showed top hits, followed by rs723432 (P allele =0.007; uncorrected) in the GPHN gene. All three were significantly associated with schizophrenia and survived gene-wide multiple testing. Haplotypes containing associated variants in GABRA1 but not GPHN were significantly associated with schizophrenia. To conclude, we provided substantiating genetic evidence for the involvement of the GABAergic system in schizophrenia susceptibility. These results warrant further investigations to replicate the association of GABRA1 and GPHN with schizophrenia and to discern the precise mechanisms of disease pathophysiology. Copyright © 2017 Elsevier B.V. All rights reserved.

No evidence that common genetic risk variation is shared between schizophrenia and autism

NARCIS (Netherlands)

Vorstman, Jacob A. S.; Anney, Richard J. L.; Derks, Eske M.; Gallagher, Louise; Gill, Michael; de Jonge, Maretha V.; van Engeland, Herman; Kahn, René S.; Ophoff, Roel A.

2013-01-01

The similarity between aspects of the clinical presentation of schizophrenia and autism spectrum disorders (ASD) suggests that elements of the biological etiology may also be shared between these two disorders. Recently, an increasing number of rare, mostly structural genetic variants are reported

Concerns about Genetic Testing for Schizophrenia among Young Adults at Clinical High Risk for Psychosis.

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Lawrence, Ryan E; Friesen, Phoebe; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

Genetic tests for schizophrenia may introduce risks and benefits. Among young adults at clinical high-risk for psychosis, little is known about their concerns and how they assess potential risks. We conducted semi-structured interviews with 15 young adults at clinical high-risk for psychosis to ask about their concerns. Participants expressed concerns about test reliability, data interpretation, stigma, psychological harm, family planning, and privacy. Participants' responses showed some departure from the ethics literature insofar as participants were primarily interested in reporting their results to people to whom they felt emotionally close, and expressed little consideration of biological closeness. Additionally, if tests showed an increased genetic risk for schizophrenia, four clinical high-risk persons felt obligated to tell an employer and another three would "maybe" tell an employer, even in the absence of clinical symptoms. These findings suggest opportunities for clinicians and genetic counselors to intervene with education and support.

Association of CCL11 promoter polymorphisms with schizophrenia in a Korean population.

Science.gov (United States)

Kang, Won Sub; Kim, Young Jong; Park, Hae Jeong; Kim, Su Kang; Paik, Jong-Woo; Kim, Jong Woo

2018-05-20

Immunological alterations and dysregulation of the inflammatory response have been suggested to play a crucial role in schizophrenia pathophysiology. Growing evidence supports the involvement of chemokines in brain development, thus many chemokines have been studied in relation with schizophrenia. The C-C motif chemokine ligand 11 (CCL11) has been shown to be related with synaptic plasticity and neurogenesis. Moreover, altered levels of CCL11 have been observed in schizophrenia patients. Therefore, we examined whether single nucleotide polymorphisms (SNPs) of the CCL11 in the promoter region contribute to susceptibility to schizophrenia. Four promoter SNPs [rs17809012 (-384T>C), rs16969415 (-426C>T), rs17735961 (-488C>A), and rs4795896 (576G>A)] were genotyped in 254 schizophrenia patients and 405 control subjects using Fluidigm SNPtype assays. The genotype frequency of CCL11 rs4795896 (-576G>A) showed significant association with schizophrenia in a recessive model (AA vs. GG/AG, p schizophrenia (p schizophrenia (p = 0.0044, p schizophrenia in a Korean population. Copyright © 2018 Elsevier B.V. All rights reserved.

SCHIZOPHRENIA: A REVIEW

OpenAIRE

Parle Milind; Sharma Kailash

2013-01-01

Schizophrenia continues to be a mysterious disease fascinating the minds of psychiatrists, pharmacologists and neuroscientists all over the world for more than a century. The crucial welfare of the millions afflicted with schizophrenia is at stake. The cause of schizophrenia is not yet identified. However, it appears from the available reports that schizophrenia results from genetic, occupational and environmental risk factors, which act independently or combine synergistically to develop sch...

Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

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Francesca Managò

2016-08-01

Full Text Available Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.

Biological study in schizophrenia

International Nuclear Information System (INIS)

Kasai, Kiyoto; Yoshikawa, Akane; Natsubori, Takanobu; Koike, Shinsuke; Nagai, Tatsuya; Araki, Tsuyoshi; Nishimura, Yukika; Iwamoto, Kazuya

2012-01-01

Schizophrenia is associated with enormous morbidity, mortality, personal disability, and social cost. Although considerable research on schizophrenia has been performed, the etiology of this disease has not been fully elucidated. In recent years, imaging and genetic technologies have been developed dramatically. Disturbances in glutamate and gamma-aminobutyric acid (GABA)ergic neurotransmission may underlie the pathophysiology of schizophrenia. We attempted an integrative review, of studies pertaining to recent advances of schizophrenia research with a focus on neuroimaging and genetic studies. Additionally, we present the preliminary findings of the clinical research in our outpatient unit, specialized for early intervention, at the University of Tokyo Hospital. (author)

[Relationship between genetic polymorphisms of 3 SNP loci in 5-HTT gene and paranoid schizophrenia].

Science.gov (United States)

Xuan, Jin-Feng; Ding, Mei; Pang, Hao; Xing, Jia-Xin; Sun, Yi-Hua; Yao, Jun; Zhao, Yi; Li, Chun-Mei; Wang, Bao-Jie

2012-12-01

To investigate the population genetic data of 3 SNP loci (rs25533, rs34388196 and rs1042173) of 5-hydroxytryptamine transporter (5-HTT) gene and the association with paranoid schizophrenia. Three SNP loci of 5-HTT gene were examined in 132 paranoid schizophrenia patients and 150 unrelated healthy individuals of Northern Chinese Han population by PCR-RFLP technique. The Hardy-Weinberg equilibrium test was performed using the chi-square test and the data of haplotype frequency and population genetics parameters were statistically analyzed. Among these three SNP loci, four haplotypes were obtained. There were no statistically significant differences between the patient group and the control group (P > 0.05). The DP values of the 3 SNP loci were 0.276, 0.502 and 0.502. The PIC of them were 0.151, 0.281 and 0.281. The PE of them were 0.014, 0.072 and 0.072. The three SNP loci and four haplotypes of 5-HTT gene have no association with paranoid schizophrenia, while the polymorphism still have high potential application in forensic practice.

Genetics, Cognition and Neurobiology of Schizotypal Personality: A Review of the Overlap with Schizophrenia

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Ulrich eEttinger

2014-02-01

Full Text Available Schizotypy refers to a set of temporally stable traits that are observed in the general population and that resemble the signs and symptoms of schizophrenia. Here, we review evidence from studies on genetics, cognition, perception, motor and oculomotor control, brain structure, brain function and psychopharmacology in schizotypy. We specifically focused on identifying areas of overlap between schizotypy and schizophrenia. Evidence was corroborated that significant overlap exists between the two, covering the behavioural, brain structural and functional as well molecular levels. In particular, several studies showed that individuals with high levels of schizotypal traits exhibit alterations in neurocognitive task performance and underlying brain function similar to the deficits seen in patients with schizophrenia. Studies of brain structure have shown both volume reductions and increases in schizotypy, pointing to schizophrenia-like deficits as well as possible protective or compensatory mechanisms. Experimental pharmacological studies have shown that high levels of schizotypy are associated with (i enhanced dopaminergic response in striatum following administration of amphetamine and (ii improvement of cognitive performance following administration of antipsychotic compounds. Together, this body of work suggests that schizotypy shows overlap with schizophrenia across multiple behavioural and neurobiological domains, suggesting that the study of schizotypal traits may be useful in improving our understanding of the aetiology of schizophrenia.

A review of schizophrenia research in malaysia.

Science.gov (United States)

Chee, K Y; Salina, A A

2014-08-01

Research in schizophrenia has advanced tremendously. One hundred and seventy five articles related to Schizophrenia were found from a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. This project aims to examine published research articles, in local and international journals in order to provide a glimpse of the research interest in Malaysia with regards to schizophrenia. Single case study, case series report, reviews and registry reports were not included in this review. Medication trial, unless it concerned a wider scope of psychopharmacology was also excluded from this review. A total of 105 articles were included in this review. Despite numerous genetics studies conducted and published, a definitive conclusion on the aetiology or mechanism underlying schizophrenia remains elusive. The National Mental Health - Schizophrenia Registry (NMHR) proved to be an important platform for many studies and publications. Studies stemmed from NMHR have provided significant insight into the baseline characteristic of patients with schizophrenia, pathway to care, and outcomes of the illness. International and regional collaborations have also encouraged important work involving stigma and discrimination in schizophrenia. Ministry of Health's hospitals (MOH) are the main research sites in the country with regards to schizophrenia research. Numbers of schizophrenia research are still low in relation to the number of universities and hospitals in the country. Some of the weaknesses include duplication of studies, over-emphasising clinical trials and ignoring basic clinical research, and the lack of publications in international and regional journals.

Risk architecture of schizophrenia: the role of epigenetics.

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Svrakic, Dragan M; Zorumski, Charles F; Svrakic, Nenad M; Zwir, Igor; Cloninger, Claude R

2013-03-01

To systematize existing data and review new findings on the cause of schizophrenia and outline an improved mixed model of schizophrenia risk. Multiple and variable genetic and environmental factors interact to influence the risk of schizophrenia. Both rare variants with large effect and common variants with small effect contribute to genetic risk of schizophrenia, with no indication for differential impact on its clinical features. Accumulating evidence supports a genetic architecture of schizophrenia with multiple scenarios, including additive polygenic, heterogeneity, and mixed polygenic-heterogeneity. The epigenetic mechanisms that mediate gene-environment (GxE) interactions provide a framework to incorporate environmental factors into models of schizophrenia risk. Environmental pathogens with small effect on risk have robust effects in the context of family history of schizophrenia. Hence, genetic risk for schizophrenia may be expressed in part as sensitivity to environmental factors. We propose an improved mixed model of schizophrenia risk in which abnormal epigenetic states with large effects are superimposed on a polygenic liability to schizophrenia. This scenario can account for GxE interactions and shared family environment, which in many cases are not explained by a single structural variant of large effect superimposed on polygenes (the traditional mixed model).

Clustering by neurocognition for fine-mapping of the schizophrenia susceptibility loci on chromosome 6p

Science.gov (United States)

Lin, Sheng-Hsiang; Liu, Chih-Min; Liu, Yu-Li; Fann, Cathy Shen-Jang; Hsiao, Po-Chang; Wu, Jer-Yuarn; Hung, Shuen-Iu; Chen, Chun-Houh; Wu, Han-Ming; Jou, Yuh-Shan; Liu, Shi K.; Hwang, Tzung J.; Hsieh, Ming H.; Chang, Chien-Ching; Yang, Wei-Chih; Lin, Jin-Jia; Chou, Frank Huang-Chih; Faraone, Stephen V.; Tsuang, Ming T.; Hwu, Hai-Gwo; Chen, Wei J.

2009-01-01

Chromosome 6p is one of the most commonly implicated regions in the genome-wide linkage scans of schizophrenia, whereas further association studies for markers in this region were inconsistent likely due to heterogeneity. This study aimed to identify more homogeneous subgroups of families for fine mapping on regions around markers D6S296 and D6S309 (both in 6p24.3) as well as D6S274 (in 6p22.3) by means of similarity in neurocognitive functioning. A total of 160 families of patients with schizophrenia comprising at least two affected siblings who had data for 8 neurocognitive test variables of the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) were subjected to cluster analysis with data visualization using the test scores of both affected siblings. Family clusters derived were then used separately in family-based association tests for 64 single nucleotide polymorphisms covering the region of 6p24.3 and 6p22.3. Three clusters were derived from the family-based clustering, with deficit cluster 1 representing deficit on the CPT, deficit cluster 2 representing deficit on both the CPT and the WCST, and a third cluster of non-deficit. After adjustment using false discovery rate for multiple testing, SNP rs13873 and haplotype rs1225934-rs13873 on BMP6-TXNDC5 genes were significantly associated with schizophrenia for the deficit cluster 1 but not for the deficit cluster 2 or non-deficit cluster. Our results provide further evidence that the BMP6-TXNDC5 locus on 6p24.3 may play a role in the selective impairments on sustained attention of schizophrenia. PMID:19694819

Identification of susceptibility genes for bipolar affective disorder and schizophrenia on chromosome 22q13

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Severinsen, Jacob Eg

2006-01-01

Linkage analyses suggest that chromosome 22q12-13 may harbor one or more shared susceptibility loci for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of distantly related cases and control individuals from the Faeroe Islands our group has previously reported that chromosome 22...... samples (total of 1,751 individuals), and by bioinformatic and expression analyses of a subset of disease associated genes and gene variants. In total 67 single nucleotide polymorphisms (SNPs) located in 18 positional candidate genes, and 4 microsattelite markers were investigated, using a Scottish case...

A genetic association study of the FXYD domain containing ion transport regulator 6 (FXYD6) gene, encoding phosphohippolin, in susceptibility to schizophrenia in a Japanese population.

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Ito, Yoshihito; Nakamura, Yukako; Takahashi, Nagahide; Saito, Shinichi; Aleksic, Branko; Iwata, Nakao; Inada, Toshiya; Ozaki, Norio

2008-06-13

The FXYD domain containing ion transport regulator 6 (FXYD6) gene is located within a region of chromosome 11 (11q23.3) that has been shown by a number of genome scans to be one of the most well-established linkages to schizophrenia. FXYD6 encodes the protein phosphohippolin, which is primarily expressed in the brain. Phosphohippolin modulates the kinetic activity of Na,K-ATPase and has long-term physiological importance in maintaining cation homeostasis. A recent study reported that FXYD6 was associated with schizophrenia in the United Kingdom samples. Applying the gene-based association concept, we carried out an association study regarding FXYD6 and schizophrenia in a Japanese population, with a sample consisting of 2026 subjects (906 schizophrenics and 1120 controls). After linkage disequilibrium analysis, 23 single nucleotide polymorphisms (SNPs) were genotyped using 5'-exonuclease allelic discrimination assay. We found a significant association of two SNPs (rs11216573; genotypic P value: 0.022 and rs555577; genotypic P value: 0.026, allelic P value: 0.011, uncorrected). Nominal P values did not survive correction for multiple testing (rs11216573; genotypic P value: 0.47 and rs555577; genotypic P value: 0.55, allelic P value: 0.24, after SNPSpD correction). No association was observed between schizophrenia patients and controls in allelic, genotypic and haplotypic analyses. Our findings suggest that FXYD6 is unlikely to be related to the development of schizophrenia in a Japanese population.

Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia

Science.gov (United States)

2013-01-01

Background The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate. Discussion Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research. Summary For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis. PMID:23672587

Genetics of Schizophrenia: Historical Insights and Prevailing Evidence.

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van de Leemput, J; Hess, J L; Glatt, S J; Tsuang, M T

2016-01-01

Schizophrenia's (SZ's) heritability and familial transmission have been known for several decades; however, despite the clear evidence for a genetic component, it has been very difficult to pinpoint specific causative genes. Even so genetic studies have taught us a lot, even in the pregenomic era, about the molecular underpinnings and disease-relevant pathways. Recurring themes emerged revealing the involvement of neurodevelopmental processes, glutamate regulation, and immune system differential activation in SZ etiology. The recent emergence of epigenetic studies aimed at shedding light on the biological mechanisms underlying SZ has provided another layer of information in the investigation of gene and environment interactions. However, this epigenetic insight also brings forth another layer of complexity to the (epi)genomic landscape such as interactions between genetic variants, epigenetic marks-including cross-talk between DNA methylation and histone modification processes-, gene expression regulation, and environmental influences. In this review, we seek to synthesize perspectives, including limitations and obstacles yet to overcome, from genetic and epigenetic literature on SZ through a qualitative review of risk factors and prevailing hypotheses. Encouraged by the findings of both genetic and epigenetic studies to date, as well as the continued development of new technologies to collect and interpret large-scale studies, we are left with a positive outlook for the future of elucidating the molecular genetic mechanisms underlying SZ and other complex neuropsychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Genetic Analysis for Two Italian Siblings with Usher Syndrome and Schizophrenia

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Daniela Domanico; Serena Fragiotta; Paolo Trabucco; Marcella Nebbioso; Enzo Maria Vingolo

2012-01-01

Usher syndrome is a group of autosomal recessive genetic disorders characterized by deafness, retinitis pigmentosa, and sometimes vestibular areflexia. The relationship between Usher syndrome and mental disorders, most commonly a “schizophrenia-like” psychosis, is sometimes described in the literature. The etiology of psychiatric expression of Usher syndrome is still unclear. We reported a case of two natural siblings with congenital hypoacusis, retinitis pigmentosa, and psychiatric symptoms....

Genetic susceptibility to environmental toxicants

DEFF Research Database (Denmark)

2001-01-01

The toxicological challenges to the chemical industry have in recent years been greatly affected by the rapid innovation and development of analytical, molecular and genetic technologies. ECETOC recognises the importance of developing the technical and intellectual skill bases in academia...... and industrial based laboratories to meet the rapid development of the science base of toxicology. As the technology to determine genetic susceptibility develops, so scientist will be able to describe altered gene expression provoked by chemicals long before they are able to offer valid interpretations...... to take toxicological data and both interpret and extrapolate it in a manner as to cause exaggerated concern. The challenge to the toxicologist is to explain what data means and in a way that inspires the confidence in those who have to apply data to the assessment of hazard and risk management. It seems...

The role of host genetics in susceptibility to influenza: a systematic review.

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Peter Horby

Full Text Available The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380.PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.The fundamental question "Is susceptibility to severe influenza in humans heritable?" remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.

Association between forkhead-box P2 gene polymorphism and clinical symptoms in chronic schizophrenia in a Chinese population.

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Rao, Wenwang; Du, Xiangdong; Zhang, Yingyang; Yu, Qiong; Hui, Li; Yu, Yaqin; Kou, Changgui; Yin, Guangzhong; Zhu, Xiaomin; Man, Lijuan; Soares, Jair C; Zhang, Xiang Yang

2017-07-01

The forkhead-box P2 (FOXP2) gene polymorphism has been reported to be involved in the susceptibility to schizophrenia; however, few studies have investigated the association between FOXP2 gene polymorphism and clinical symptoms in schizophrenia. This study investigated whether the FOXP2 gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese population. The FOXP2 rs10447760 polymorphism was genotyped in 1069 schizophrenia inpatients and 410 healthy controls using a case-control design. The patients' psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the genotype and allele distributions between the patient and control groups. Interestingly, we found significant differences in PANSS total, positive symptom, and general psychopathology scores between genotypic subgroups in patients, with the higher score in patients with CC genotype than those with CT genotype (all p schizophrenia, but may contribute to the clinical symptoms of schizophrenia among Han Chinese.

Deficits in implicit attention to social signals in schizophrenia and high risk groups: behavioural evidence from a new illusion.

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Mascha van 't Wout

Full Text Available BACKGROUND: An increasing body of evidence suggests that the apparent social impairments observed in schizophrenia may arise from deficits in social cognitive processing capacities. The ability to process basic social cues, such as gaze direction and biological motion, effortlessly and implicitly is thought to be a prerequisite for establishing successful social interactions and for construing a sense of "social intuition." However, studies that address the ability to effortlessly process basic social cues in schizophrenia are lacking. Because social cognitive processing deficits may be part of the genetic vulnerability for schizophrenia, we also investigated two groups that have been shown to be at increased risk of developing schizophrenia-spectrum pathology: first-degree relatives of schizophrenia patients and men with Klinefelter syndrome (47,XXY. RESULTS: We compared 28 patients with schizophrenia, 29 siblings of patients with schizophrenia, and 29 individuals with Klinefelter syndrome with 46 matched healthy control subjects on a new paradigm. This paradigm measures one's susceptibility for a bias in distance estimation between two agents that is induced by the implicit processing of gaze direction and biological motion conveyed by these agents. Compared to control subjects, patients with schizophrenia, as well as siblings of patients and Klinefelter men, showed a lack of influence of social cues on their distance judgments. CONCLUSIONS: We suggest that the insensitivity for social cues is a cognitive aspect of schizophrenia that may be seen as an endophenotype as it appears to be present both in relatives who are at increased genetic risk and in a genetic disorder at risk for schizophrenia-spectrum psychopathology. These social cue-processing deficits could contribute, in part, to the difficulties in higher order social cognitive tasks and, hence, to decreased social competence that has been observed in these groups.

Deficits in implicit attention to social signals in schizophrenia and high risk groups: behavioural evidence from a new illusion.

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van 't Wout, Mascha; van Rijn, Sophie; Jellema, Tjeerd; Kahn, René S; Aleman, André

2009-01-01

An increasing body of evidence suggests that the apparent social impairments observed in schizophrenia may arise from deficits in social cognitive processing capacities. The ability to process basic social cues, such as gaze direction and biological motion, effortlessly and implicitly is thought to be a prerequisite for establishing successful social interactions and for construing a sense of "social intuition." However, studies that address the ability to effortlessly process basic social cues in schizophrenia are lacking. Because social cognitive processing deficits may be part of the genetic vulnerability for schizophrenia, we also investigated two groups that have been shown to be at increased risk of developing schizophrenia-spectrum pathology: first-degree relatives of schizophrenia patients and men with Klinefelter syndrome (47,XXY). We compared 28 patients with schizophrenia, 29 siblings of patients with schizophrenia, and 29 individuals with Klinefelter syndrome with 46 matched healthy control subjects on a new paradigm. This paradigm measures one's susceptibility for a bias in distance estimation between two agents that is induced by the implicit processing of gaze direction and biological motion conveyed by these agents. Compared to control subjects, patients with schizophrenia, as well as siblings of patients and Klinefelter men, showed a lack of influence of social cues on their distance judgments. We suggest that the insensitivity for social cues is a cognitive aspect of schizophrenia that may be seen as an endophenotype as it appears to be present both in relatives who are at increased genetic risk and in a genetic disorder at risk for schizophrenia-spectrum psychopathology. These social cue-processing deficits could contribute, in part, to the difficulties in higher order social cognitive tasks and, hence, to decreased social competence that has been observed in these groups.

Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants.

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Hauberg, Mads Engel; Roussos, Panos; Grove, Jakob; Børglum, Anders Dupont; Mattheisen, Manuel

2016-04-01

The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes. To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation. The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes. Results from association tests for miRNA targetomes and related analyses. In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.

Psychosis among "healthy" siblings of schizophrenia patients

OpenAIRE

Arajärvi, Ritva; Ukkola, Jonna; Haukka, Jari; Suvisaari, Jaana; Hintikka, Jukka; Partonen, Timo; Lönnqvist, Jouko

2006-01-01

Abstract Background Schizophrenia aggregates in families and accurate diagnoses are essential for genetic studies of schizophrenia. In this study, we investigated whether siblings of patients with schizophrenia can be identified as free of any psychotic disorder using only register information. We also analyzed the emergence of psychotic disorders among siblings of patients with schizophrenia during seven to eleven years of follow-up. Methods A genetically homogenous population isolate in no...

Mediation and modification of genetic susceptibility to obesity by eating behaviors.

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de Lauzon-Guillain, Blandine; Clifton, Emma Ad; Day, Felix R; Clément, Karine; Brage, Soren; Forouhi, Nita G; Griffin, Simon J; Koudou, Yves Akoli; Pelloux, Véronique; Wareham, Nicholas J; Charles, Marie-Aline; Heude, Barbara; Ong, Ken K

2017-10-01

Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health. Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity. Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des déterminants pré et postnatals de la santé et du développement de l'enfant) population-based cohort studies, respectively. The eating behaviors-emotional eating, uncontrolled eating, and cognitive restraint-were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI. Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P- Sobel = 0.01; Fenland: P- Sobel = 0.02) and uncontrolled eating (EDEN: P- Sobel = 0.04; Fenland: P -Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association ( P -Sobel > 0.10), except among EDEN women ( P -Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P -interaction = 0.0001; Fenland: P -interaction = 0.04) and Fenland women ( P -interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile. Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social-communication difficulties

OpenAIRE

St Pourcain, B.; Robinson, E.; Anttila, V.; Sullivan, B.; Maller, J.; Golding, J.; Skuse, D.; Ring, S.; Evans, D.; Zammit, S.; Fisher, S.; Neale, B.; Anney, R.; Ripke, S.; Hollegaard, M.

2017-01-01

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and\\ud schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early\\ud childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether\\ud overlap in common genetic influences between these clinical conditions and impairments in social communication depends ...

The environment and susceptibility to schizophrenia.

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Brown, Alan S

2011-01-01

In the present article the putative role of environmental factors in schizophrenia is reviewed and synthesized. Accumulating evidence from recent studies suggests that environmental exposures may play a more significant role in the etiopathogenesis of this disorder than previously thought. This expanding knowledge base is largely a consequence of refinements in the methodology of epidemiologic studies, including birth cohort investigations, and in preclinical research that has been inspired by the evolving literature on animal models of environmental exposures. This paper is divided into four sections. In the first, the descriptive epidemiology of schizophrenia is reviewed. This includes general studies on incidence, prevalence, and differences in these measures by urban-rural, neighborhood, migrant, and season of birth status, as well as time trends. In the second section, we discuss the contribution of environmental risk factors acting during fetal and perinatal life; these include infections [e.g. rubella, influenza, Toxoplasma gondii (T. gondii), herpes simplex virus type 2 (HSV-2)], nutritional deficiencies (e.g., famine, folic acid, iron, vitamin D), paternal age, fetal/neonatal hypoxic and other obstetric insults and complications, maternal stress and other exposures [e.g. lead, rhesus (Rh) incompatibility, maternal stress]. Other putative neurodevelopmental determinants, including cannabis, socioeconomic status, trauma, and infections during childhood and adolescence are also covered. In the third section, these findings are synthesized and their implications for prevention and uncovering biological mechanisms, including oxidative stress, apoptosis, and inflammation, are discussed. Animal models, including maternal immune activation, have yielded evidence suggesting that these exposures cause brain and behavioral phenotypes that are analogous to findings observed in patients with schizophrenia. In the final section, future studies including new, larger, and

Neurodevelopment, GABA system dysfunction, and schizophrenia.

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Schmidt, Martin J; Mirnics, Karoly

2015-01-01

The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

Science.gov (United States)

Schmidt, Martin J; Mirnics, Karoly

2015-01-01

The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system. PMID:24759129

GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

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Naveen S. Khanzada

2017-02-01

Full Text Available Bipolar disorder (BPD and schizophrenia (SCH show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes, BPD (290 genes and SCH (560 genes. Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways. Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0, Amphetamine addiction (five genes, score = 24.2, and Sudden infant death syndrome (six genes, score = 24.1. Brain tissues included the medulla oblongata (11 genes, score = 2.1, thalamus (10 genes, score = 2.0 and hypothalamus (nine genes, score = 2.0 with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2. Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

OpenAIRE

Schmidt, Martin J; Mirnics, Karoly

2014-01-01

The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and...

Genetic mouse models relevant to schizophrenia: taking stock and looking forward.

Science.gov (United States)

Harrison, Paul J; Pritchett, David; Stumpenhorst, Katharina; Betts, Jill F; Nissen, Wiebke; Schweimer, Judith; Lane, Tracy; Burnet, Philip W J; Lamsa, Karri P; Sharp, Trevor; Bannerman, David M; Tunbridge, Elizabeth M

2012-03-01

Genetic mouse models relevant to schizophrenia complement, and have to a large extent supplanted, pharmacological and lesion-based rat models. The main attraction is that they potentially have greater construct validity; however, they share the fundamental limitations of all animal models of psychiatric disorder, and must also be viewed in the context of the uncertain and complex genetic architecture of psychosis. Some of the key issues, including the choice of gene to target, the manner of its manipulation, gene-gene and gene-environment interactions, and phenotypic characterization, are briefly considered in this commentary, illustrated by the relevant papers reported in this special issue. Copyright © 2011 Elsevier Ltd. All rights reserved.

The genetic and environmental determinants of the association between brain abnormalities and schizophrenia: the schizophrenia twins and relatives consortium.

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van Haren, Neeltje E M; Rijsdijk, Fruhling; Schnack, Hugo G; Picchioni, Marco M; Toulopoulou, Timothea; Weisbrod, Matthias; Sauer, Heinrich; van Erp, Theo G; Cannon, Tyrone D; Huttunen, Matti O; Boomsma, Dorret I; Hulshoff Pol, Hilleke E; Murray, Robin M; Kahn, Rene S

2012-05-15

Structural brain abnormalities are consistently found in schizophrenia (Sz) and have been associated with the familial risk for the disorder. We aim to define the relative contributions of genetic and nongenetic factors to the association between structural brain abnormalities and Sz in a uniquely powered cohort (Schizophrenia Twins and Relatives consortium). An international multicenter magnetic resonance imaging collaboration was set up to pool magnetic resonance imaging scans from twin pairs in Utrecht (The Netherlands), Helsinki (Finland), London (United Kingdom), and Jena (Germany). A sample of 684 subjects took part, consisting of monozygotic twins (n = 410, with 51 patients from concordant and 52 from discordant pairs) and dizygotic twins (n = 274, with 39 patients from discordant pairs). The additive genetic, common, and unique environmental contributions to the association between brain volumes and risk for Sz were estimated by structural equation modeling. The heritabilities of most brain volumes were significant and ranged between 52% (temporal cortical gray matter) and 76% (cerebrum). Heritability of cerebral gray matter did not reach significance (34%). Significant phenotypic correlations were found between Sz and reduced volumes of the cerebrum (-.22 [-.30/-.14]) and white matter (-.17 [-.25/-.09]) and increased volume of the third ventricle (.18 [.08/.28]). These were predominantly due to overlapping genetic effects (77%, 94%, and 83%, respectively). Some of the genes that transmit the risk for Sz also influence cerebral (white matter) volume. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

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Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S; Clohisey, Sara; Gray, Alan; Neyton, Lucile P A; Barrett, Jeffrey; Stahl, Eli A; Tenesa, Albert; Andersson, Robin; Brown, J Ben; Faulkner, Geoffrey J; Lizio, Marina; Schaefer, Ulf; Daub, Carsten; Itoh, Masayoshi; Kondo, Naoto; Lassmann, Timo; Kawai, Jun; Mole, Damian; Bajic, Vladimir B; Heutink, Peter; Rehli, Michael; Kawaji, Hideya; Sandelin, Albin; Suzuki, Harukazu; Satsangi, Jack; Wells, Christine A; Hacohen, Nir; Freeman, Thomas C; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R; Hume, David A

2018-03-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

Genetic and genomic analysis modeling of germline c-MYC overexpression and cancer susceptibility

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Nunes Virginia

2008-01-01

Full Text Available Abstract Background Germline genetic variation is associated with the differential expression of many human genes. The phenotypic effects of this type of variation may be important when considering susceptibility to common genetic diseases. Three regions at 8q24 have recently been identified to independently confer risk of prostate cancer. Variation at 8q24 has also recently been associated with risk of breast and colorectal cancer. However, none of the risk variants map at or relatively close to known genes, with c-MYC mapping a few hundred kilobases distally. Results This study identifies cis-regulators of germline c-MYC expression in immortalized lymphocytes of HapMap individuals. Quantitative analysis of c-MYC expression in normal prostate tissues suggests an association between overexpression and variants in Region 1 of prostate cancer risk. Somatic c-MYC overexpression correlates with prostate cancer progression and more aggressive tumor forms, which was also a pathological variable associated with Region 1. Expression profiling analysis and modeling of transcriptional regulatory networks predicts a functional association between MYC and the prostate tumor suppressor KLF6. Analysis of MYC/Myc-driven cell transformation and tumorigenesis substantiates a model in which MYC overexpression promotes transformation by down-regulating KLF6. In this model, a feedback loop through E-cadherin down-regulation causes further transactivation of c-MYC. Conclusion This study proposes that variation at putative 8q24 cis-regulator(s of transcription can significantly alter germline c-MYC expression levels and, thus, contribute to prostate cancer susceptibility by down-regulating the prostate tumor suppressor KLF6 gene.

Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia.

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Buhusi, Mona; Obray, Daniel; Guercio, Bret; Bartlett, Mitchell J; Buhusi, Catalin V

2017-08-30

Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the 'two-hit' theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a 'two-hit' (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments. Copyright © 2017 Elsevier B.V. All rights reserved.

Host genetics in granuloma formation: human-like lung pathology in mice with reciprocal genetic susceptibility to M. tuberculosis and M. avium.

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Elena Kondratieva

2010-05-01

Full Text Available Development of lung granulomata is a hallmark of infections caused by virulent mycobacteria, reflecting both protective host response that restricts infection spreading and inflammatory pathology. The role of host genetics in granuloma formation is not well defined. Earlier we have shown that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis but resistant to M. avium infection, whereas B6 mice show a reversed pattern of susceptibility. Here, by directly comparing: (i characteristics of susceptibility to two infections in vivo; (ii architecture of lung granulomata assessed by immune staining; and (iii expression of genes encoding regulatory factors of neutrophil influx in the lung tissue, we demonstrate that genetic susceptibility of the host largely determines the pattern of lung pathology. Necrotizing granuloma surrounded by hypoxic zones, as well as a massive neutrophil influx, develop in the lungs of M. avium-infected B6 mice and in the lungs of M. tuberculosis-infected I/St mice, but not in the lungs of corresponding genetically resistant counterparts. The mirror-type lung tissue responses to two virulent mycobacteria indicate that the level of genetic susceptibility of the host to a given mycobacterial species largely determines characteristics of pathology, and directly demonstrate the importance of host genetics in pathogenesis.

Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.

Science.gov (United States)

Roffman, Joshua L; Brohawn, David G; Nitenson, Adam Z; Macklin, Eric A; Smoller, Jordan W; Goff, Donald C

2013-03-01

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.

The role of schizotypy in the study of the etiology of schizophrenia spectrum disorders.

Science.gov (United States)

Barrantes-Vidal, Neus; Grant, Phillip; Kwapil, Thomas R

2015-03-01

Schizotypy provides a useful construct for understanding the development of schizophrenia spectrum disorders. As research on the epidemiology of psychotic symptoms and clinical risk for psychosis has expanded, conceptual challenges have emerged to comprehend the nature and borders of the space comprised between personality variation and psychosis. Schizotypy is considered in light of these more recent constructs. It is suggested that rather than being superseded by them due to their higher specificity and predictive power for transition to psychosis, schizotypy integrates them as it constitutes a dynamic continuum ranging from personality to psychosis. The advantages of schizotypy for studying schizophrenia etiology are discussed (eg, it facilitates a developmental approach and the identification of causal, resilience, and compensating factors and offers a multidimensional structure that captures etiological heterogeneity). An overview of putative genetic, biological, and psychosocial risk factors is presented, focusing on communalities and differences between schizotypy and schizophrenia spectrum disorders. The found notable overlap supports etiological continuity, and, simultaneously, differential findings appear that are critical to understanding resilience to schizophrenia. For example, discrepant findings in genetic studies might be interpreted as suggestive of sets of independent genetic factors playing a differential role in schizotypy and schizophrenia: some would influence variation specifically on schizotypy dimensions (ie, high vs low schizotypy, thereby increasing proneness to psychosis), some would confer unspecific liability to disease by impacting neural properties and susceptibility to environmental factors (ie, high vs low resilience to disorder) and some might contribute to disease-specific characteristics. Finally, schizotypy's promise for studying gene-environment interactions is considered. © The Author 2015. Published by Oxford University

Schizophrenia : Current concepts in aetiology

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P S Bhat

2014-01-01

Full Text Available Schizophrenia is perhaps the most devastating neuropsychiatric illness. Worldwide, its prevalence rate is about 1%. Schizophrenia is considered a neurodevelopmental disorder involving the interplay of susceptibility genes and environmental factors. There is a wide range of pathologic findings, but there is no specific or diagnostic laboratory abnormality. Till date, the aetiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Over the last forty years, the dopaminergic model has been the leading neurochemical hypothesis of schizophrenia. Yet it remains unlikely that dopaminergic dysfunction, on its own. Glutamatergic models provide an alternate approach for conceptualizing the brain abnormalities associated with schizophrenia. New pharmacological and behavioral approaches aimed at potentiating glutamatergic neurotransmission, offer new hopeforfuture clinical development

Regional gray matter abnormalities in patients with schizophrenia determined with optimized voxel-based morphometry

Science.gov (United States)

Guo, XiaoJuan; Yao, Li; Jin, Zhen; Chen, Kewei

2006-03-01

This study examined regional gray matter abnormalities across the whole brain in 19 patients with schizophrenia (12 males and 7 females), comparing with 11 normal volunteers (7 males and 4 females). The customized brain templates were created in order to improve spatial normalization and segmentation. Then automated preprocessing of magnetic resonance imaging (MRI) data was conducted using optimized voxel-based morphometry (VBM). The statistical voxel based analysis was implemented in terms of two-sample t-test model. Compared with normal controls, regional gray matter concentration in patients with schizophrenia was significantly reduced in the bilateral superior temporal gyrus, bilateral middle frontal and inferior frontal gyrus, right insula, precentral and parahippocampal areas, left thalamus and hypothalamus as well as, however, significant increases in gray matter concentration were not observed across the whole brain in the patients. This study confirms and extends some earlier findings on gray matter abnormalities in schizophrenic patients. Previous behavior and fMRI researches on schizophrenia have suggested that cognitive capacity decreased and self-conscious weakened in schizophrenic patients. These regional gray matter abnormalities determined through structural MRI with optimized VBM may be potential anatomic underpinnings of schizophrenia.

Evolution, revolution and heresy in the genetics of infectious disease susceptibility

Science.gov (United States)

Hill, Adrian V. S.

2012-01-01

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case–control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference. PMID:22312051

Evolution, revolution and heresy in the genetics of infectious disease susceptibility.

Science.gov (United States)

Hill, Adrian V S

2012-03-19

Infectious pathogens have long been recognized as potentially powerful agents impacting on the evolution of human genetic diversity. Analysis of large-scale case-control studies provides one of the most direct means of identifying human genetic variants that currently impact on susceptibility to particular infectious diseases. For over 50 years candidate gene studies have been used to identify loci for many major causes of human infectious mortality, including malaria, tuberculosis, human immunodeficiency virus/acquired immunodeficiency syndrome, bacterial pneumonia and hepatitis. But with the advent of genome-wide approaches, many new loci have been identified in diverse populations. Genome-wide linkage studies identified a few loci, but genome-wide association studies are proving more successful, and both exome and whole-genome sequencing now offer a revolutionary increase in power. Opinions differ on the extent to which the genetic component to common disease susceptibility is encoded by multiple high frequency or rare variants, and the heretical view that most infectious diseases might even be monogenic has been advocated recently. Review of findings to date suggests that the genetic architecture of infectious disease susceptibility may be importantly different from that of non-infectious diseases, and it is suggested that natural selection may be the driving force underlying this difference.

Sex differences in the course of schizophrenia across diverse regions of the world

Directory of Open Access Journals (Sweden)

Novick D

2016-11-01

Full Text Available Diego Novick,1 William Montgomery,2 Tamas Treuer,3 Maria Victoria Moneta,4 Josep Maria Haro4 1Eli Lilly and Company, Windlesham, Surrey, UK; 2Eli Lilly Australia Pty Ltd, West Ryde, NSW, Australia; 3Eli Lilly and Company, Neuroscience Research, Budapest, Hungary; 4Parc Sanitari Sant Joan de Déu, CIBERSAM, Universitat de Barcelona, Barcelona, Spain Abstract: This study explores sex differences in the outcomes of patients with schizophrenia (clinical/functional remission and recovery across diverse regions of the world (Northern Europe, Southern Europe, Central and Eastern Europe, Latin America, East Asia, and North Africa and the Middle East. Data (n=16,380 for this post hoc analysis were taken from the World-Schizophrenia Health Outcomes Study. In most regions, females had a later age at first service contact for schizophrenia, a lower level of overall/negative symptom severity, lower rates of alcohol/substance abuse and paid employment, and higher percentages of having a spouse/partner and independent living. Overall, females had slightly higher rates of clinical remission (58.0% vs 51.8%, functional remission (22.8% vs 16.0%, and recovery (16.5% vs 16.0% at 36 months (P<0.001 for all. This pattern was consistently observed in Southern Europe and Northern Europe even after controlling for baseline sex differences, but not in other regions. In Central and Eastern Europe, rates of clinical remission were higher in females at 36 months, but those of functional remission and recovery were similar between males and females. The opposite was observed for Latin America. In East Asia, sex differences were rarely observed for these outcomes. Finally, in North Africa and the Middle East, sex differences in these outcomes were pronounced only in regression analyses. These regional variations shed light on the importance of psychosocial and cultural factors and their effects on sex in the prognosis of schizophrenia. Keywords: sex, remission, recovery

Genetic susceptibility to pancreatic cancer and its functional characterisation: The PANcreatic Disease ReseArch (PANDoRA) consortium

Czech Academy of Sciences Publication Activity Database

Campa, D.; Rizzato, C.; Capurso, G.; Giese, N.; Funel, N.; Greenhalf, W.; Souček, P.; Gazouli, M.; Pezzilli, R.; Pasquali, C.; Talar-Wojnarowska, R.; Cantore, M.; Andriulli, A.; Scarpa, A.; Jamroziak, K.; Delle Fave, G.; Costello, E.; Khaw, K. T.; Heller, A.; Key, T. K.; Theodoropoulos, G.; Malecka-Panas, E.; Mambrini, A.; Bambi, F.; Landi, S.; Pedrazzoli, S.; Bassi, C.; Pacetti, P.; Piepoli, A.; Tavano, F.; di Sebastiano, P.; Vodičková, Ludmila; Basso, D.; Plebani, M.; Fogar, P.; Buechler, M. W.; Bugert, P.; Vodička, Pavel; Boggi, U.; Neoptolemos, J. P.; Werner, J.; Canzian, F.

2013-01-01

Roč. 45, č. 2 (2013), s. 95-99 ISSN 1590-8658 Institutional support: RVO:68378041 Keywords : cancer susceptibility * genetic polymorphisms * genetic susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.889, year: 2013

Radiation-sensitive genetically susceptible pediatric sub-populations

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Kleinerman, Ruth A. [National Cancer Institute, NIH, DHHS, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Rockville, MD (United States)

2009-02-15

Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation. (orig.)

A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia

DEFF Research Database (Denmark)

Ingason, Andrés; Giegling, Ina; Cichon, Sven

2010-01-01

The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample....... Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both...... as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia....

Targeted resequencing of regulatory regions at schizophrenia risk loci: Role of rare functional variants at chromatin repressive states.

Science.gov (United States)

González-Peñas, Javier; Amigo, Jorge; Santomé, Luis; Sobrino, Beatriz; Brenlla, Julio; Agra, Santiago; Paz, Eduardo; Páramo, Mario; Carracedo, Ángel; Arrojo, Manuel; Costas, Javier

2016-07-01

There is mounting evidence that regulatory variation plays an important role in genetic risk for schizophrenia. Here, we specifically search for regulatory variants at risk by sequencing promoter regions of twenty-three genes implied in schizophrenia by copy number variant or genome-wide association studies. After strict quality control, a total of 55,206bp per sample were analyzed in 526 schizophrenia cases and 516 controls from Galicia, NW Spain, using the Applied Biosystems SOLiD System. Variants were filtered based on frequency from public databases, chromatin states from the RoadMap Epigenomics Consortium at tissues relevant for schizophrenia, such as fetal brain, mid-frontal lobe, and angular gyrus, and prediction of functionality from RegulomeDB. The proportion of rare variants at polycomb repressive chromatin state at relevant tissues was higher in cases than in controls. The proportion of rare variants with predicted regulatory role was significantly higher in cases than in controls (P=0.0028, OR=1.93, 95% C.I.=1.23-3.04). Combination of information from both sources led to the identification of an excess of carriers of rare variants with predicted regulatory role located at polycomb repressive chromatin state at relevant tissues in cases versus controls (P=0.0016, OR=19.34, 95% C.I.=2.45-2495.26). The variants are located at two genes affected by the 17q12 copy number variant, LHX1 and HNF1B. These data strongly suggest that a specific epigenetic mechanism, chromatin remodeling by histone modification during early development, may be impaired in a subset of schizophrenia patients, in agreement with previous data. Copyright © 2016 Elsevier B.V. All rights reserved.

Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

Science.gov (United States)

2013-03-14

behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

Susceptibility Genes in Thyroid Autoimmunity

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Yoshiyuki Ban

2005-01-01

Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

Neuregulin-1 genotypes and eye movements in schizophrenia

DEFF Research Database (Denmark)

Haraldsson, H.M.; Ettinger, U.; Magnusdottir, B.B.

2010-01-01

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain...... findings of impaired AS and SPEM performance in schizophrenia patients (all P eye movement variables...

Different psychological effects of cannabis use in adolescents at genetic high risk for schizophrenia and with attention deficit/hyperactivity disorder (ADHD).

Science.gov (United States)

Hollis, Chris; Groom, Madeleine J; Das, Debasis; Calton, Tim; Bates, Alan T; Andrews, Hayley K; Jackson, Georgina M; Liddle, Peter F

2008-10-01

Controversy exists regarding whether young people at risk for schizophrenia are at increased risk of adverse mental effects of cannabis use. We examined cannabis use and mental health functioning in three groups of young people aged 14-21; 36 non-psychotic siblings of adolescents with schizophrenia (genetic high risk group), 25 adolescents with attention deficit hyperactivity disorder (ADHD) and 72 healthy controls. The groups were sub-divided into 'users' and 'non-users' of cannabis based on how often they had used cannabis previously. Mental health functioning was quantified by creating a composite index derived from scores on the Schizotypal Personality Questionnaire (SPQ), Strengths and Difficulties Questionnaire (SDQ) and Global Assessment of Function (GAF). A significant positive association between cannabis use and mental health disturbance was confined to young people at genetic high risk for schizophrenia. To determine whether the relationship was specific to particular dimensions of mental health function, a second composite index was created based on scores from the SPQ Disorganisation and SDQ hyperactivity-inattention sub-scales. Again, there was a significant positive association between cannabis use and factor scores which was specific to the genetic high risk group. There was a trend for this association to be negative in the ADHD group (p=0.07). The findings support the view that young people at genetic high risk for schizophrenia are particularly vulnerable to mental health problems associated with cannabis use. Further research is needed to investigate the basis of relationships between cannabis and mental health in genetically vulnerable individuals.

Interaction between catechol-O-methyltransferase (COMT) Val158Met genotype and genetic vulnerability to schizophrenia during explicit processing of aversive facial stimuli.

Science.gov (United States)

Lo Bianco, L; Blasi, G; Taurisano, P; Di Giorgio, A; Ferrante, F; Ursini, G; Fazio, L; Gelao, B; Romano, R; Papazacharias, A; Caforio, G; Sinibaldi, L; Popolizio, T; Bellantuono, C; Bertolino, A

2013-02-01

Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing. A total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself.

Genome-wide association study of clinical dimensions of schizophrenia

DEFF Research Database (Denmark)

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

2012-01-01

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

The GSK3B gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population.

Science.gov (United States)

Chen, Jianhua; Wang, Meng; Waheed Khan, Raja Amjad; He, Kuanjun; Wang, Qingzhong; Li, Zhiqiang; Shen, Jiawei; Song, Zhijian; Li, Wenjin; Wen, Zujia; Jiang, Yiwen; Xu, Yifeng; Shi, Yongyong; Ji, Weidong

2015-10-01

Glycogen synthease kinase-3B is a key gene encoding a protein kinase which is abundant in brain, and is involved in signal transduction cascades of neuronal cell development and energy metabolism. Previous researches proposed GSK3B as a potential region for schizophrenia. To validate the susceptibility of GSK3B to major depressive disorder, and to investigate the overlapping risk conferred by GSK3B for mental disorders, we performed a large-scale case-control study, analyzed 6 tag single nucleotide polymorphisms using TaqMan® technology in 1,045 major depressive disorder patients, 1,235 schizophrenia patients and 1,235 normal controls of Han Chinese origin. We found rs334535 (Pallele=2.79E-03, Pgenotype=5.00E-03, OR=1.429) and rs2199503 (Pallele=0.020, Pgenotype= 0.040, OR=1.157) showed association with major depressive disorder before Bonferroni correction. rs6771023 (adjusted Pallele=1.64E-03, adjusted Pgenotype=6.00E-03, OR=0.701) and rs2199503 (adjusted Pallele=0.001, adjusted Pgenotype=0.002, OR=1.251) showed significant association with schizophrenia after Bonferroni correction. rs2199503 (adjusted Pallele=1.70E-03, adjusted Pgenotype=0.006, OR=1.208) remained to be significant in the combined cases of major depressive disorder and schizophrenia after Bonferroni correction. Further validations of our findings in samples with larger scale are suggested, and functional genomic study is needed to elucidate the role of GSK3B in signal pathway and psychiatric disorders. Our results provide evidence that the GSK3B gene could be a promising region which contains genetic risk for both major depressive disorder and schizophrenia in the Han Chinese population. The study on variants conferring overlapping risk for multiple psychiatric disorders could be tangible pathogenesis support and clinical or diagnostic references. Copyright © 2015. Published by Elsevier B.V.

Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia

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Ketan K. Marballi

2018-02-01

Full Text Available While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD. Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3, early growth response 1 (EGR1 and NGFI-A Binding Protein 2 (NAB2; each of which contains the “Index single nucleotide polymorphism (SNP” (most SNP at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may

Immediate Early Genes Anchor a Biological Pathway of Proteins Required for Memory Formation, Long-Term Depression and Risk for Schizophrenia

Science.gov (United States)

Marballi, Ketan K.; Gallitano, Amelia L.

2018-01-01

While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the “Index single nucleotide polymorphism (SNP)” (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in

Seasonal fluctuation in susceptibility to insecticides within natural populations of Drosophila melanogaster. II. Features of genetic variation in susceptibility to organophosphate insecticides within natural populations of D. melanogaster.

Science.gov (United States)

Miyo, Takahiro; Oguma, Yuzuru; Charlesworth, Brian

2006-08-01

To elucidate genetic variation in susceptibility to organophosphate insecticides within natural populations of Drosophila melanogaster, we conducted an analysis of variance for mortality data sets of isofemale lines (10-286 lines) used in the previous studies. Susceptibility of isofemale lines to the three organophosphate insecticides was continuously distributed within each natural population, ranging from susceptible to resistant. Analysis of variance showed highly significant variation among isofemale lines in susceptibility to each insecticide for each natural population. Significant genetic variances in susceptibility to the three chemicals were estimated for the Katsunuma population; 0.0529-0.2722 for malathion, 0.0492-0.1603 for prothiophos, and 0.0469-0.1696 for fenitrothion. Contrary to the consistent seasonal tendency towards an increase in mean susceptibility in the fall, reported in the previous study, genetic variances in susceptibility to the three organophosphates did not change significantly in 1997 but tended to increase by 2- to 5-times in 1998. We tested whether both the observed situations, maintenance and increase in genetic variance in organophosphate resistance, can be generated under circumstances in which the levels of resistance to the three organophosphates tended to decrease, by conducting a simulation analysis, based on the hypothesis that resistant genotypes have lower fitnesses than susceptible ones under the density-independent condition. The simulation analysis generally explained the pattern in the mean susceptibility and genetic variances in susceptibility to the three organophosphates, observed in the Katsunuma population of D. melanogaster. It was suggested that the differences in the frequencies of resistance genes in the summer population could affect the patterns in genetic variance in organophosphate resistance in the fall population.

Abnormal functional motor lateralization in healthy siblings of patients with schizophrenia.

Science.gov (United States)

Altamura, Mario; Fazio, Leonardo; De Salvia, Michela; Petito, Annamaria; Blasi, Giuseppe; Taurisano, Paolo; Romano, Raffaella; Gelao, Barbara; Bellomo, Antonello; Bertolino, Alessandro

2012-07-30

Earlier neuroimaging studies of motor function in schizophrenia have demonstrated reduced functional lateralization in the motor network during motor tasks. Here, we used event-related functional magnetic resonance imaging during a visually guided motor task in 18 clinically unaffected siblings of patients with schizophrenia and 24 matched controls to investigate if abnormal functional lateralization is related to genetic risk for this brain disorder. Whereas activity associated with motor task performance was mainly contralateral with only a marginal ipsilateral component in healthy participants, unaffected siblings had strong bilateral activity with significantly greater response in ipsilateral and contralateral premotor areas as well as in contralateral subcortical motor regions relative to controls. Reduced lateralization in siblings was also identified with a measure of laterality quotient. These findings suggest that abnormal functional lateralization of motor circuitry is related to genetic risk of schizophrenia. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Nonlinkage of D6S260, a putative schizophrenia locus, to bipolar affective disorder

Energy Technology Data Exchange (ETDEWEB)

Adams, L.J.; Mitchell, P.B. [Univ. of South Wales (Australia); Salmon, J. [Garvan Institute of Medical Research, Sydney, New South Wales (Australia)] [and others

1996-09-20

To examine whether genes that predispose to schizophrenia also confer a predisposition to other psychiatric disorders such as bipolar affective disorder (BAD), we tested for linkage between the recently identified schizophrenia susceptibility locus D6S260 and the inheritance of BAD in 12 large Australian pedigrees. We found no evidence for linkage over a region of 12-27 cM from the D6S260 locus, depending on the model used. Our results therefore do not provide support for the continuum theory of psychosis. 13 refs., 2 tabs.

Genetic susceptibility to feline infectious peritonitis in Birman cats.

Science.gov (United States)

Golovko, Lyudmila; Lyons, Leslie A; Liu, Hongwei; Sørensen, Anne; Wehnert, Suzanne; Pedersen, Niels C

2013-07-01

Genetic factors are presumed to influence the incidence of feline infectious peritonitis (FIP), especially among pedigreed cats. However, proof for the existence of such factors has been limited and mainly anecdotal. Therefore, we sought evidence for genetic susceptibility to FIP using feline high density single nucleotide polymorphism (SNP) arrays in a genome-wide association study (GWAS). Birman cats were chosen for GWAS because they are highly inbred and suffer a high incidence of FIP. DNA from 38 Birman cats that died of FIP and 161 healthy cats from breeders in Denmark and USA were selected for genotyping using 63K SNPs distributed across the feline genome. Danish and American Birman cats were closely related and the populations were therefore combined and analyzed in two manners: (1) all cases (FIP) vs. all controls (healthy) regardless of age, and (2) cases 1½ years of age and younger (most susceptible) vs. controls 2 years of age and older (most resistant). GWAS of the second cohort was most productive in identifying significant genome-wide associations between case and control cats. Four peaks of association with FIP susceptibility were identified, with two being identified on both analyses. Five candidate genes ELMO1, RRAGA, TNFSF10, ERAP1 and ERAP2, all relevant to what is known about FIP virus pathogenesis, were identified but no single association was fully concordant with the disease phenotype. Difficulties in doing GWAS in cats and interrogating complex genetic traits were discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Williams syndrome deletions and duplications: Genetic windows to understanding anxiety, sociality, autism, and schizophrenia.

Science.gov (United States)

Crespi, Bernard J; Procyshyn, Tanya L

2017-08-01

We describe and evaluate an integrative hypothesis for helping to explain the major neurocognitive features of individuals with Williams syndrome region deletions and duplications. First, we demonstrate how the cognitive differences between Williams syndrome individuals, individuals with duplications of this region, and healthy individuals parallel the differences between individuals subject to effects of increased or decreased oxytocin. Second, we synthesize evidence showing that variation in expression of the gene GTF2I (General Transcription Factor II-I) underlies the primary social phenotypes of Williams syndrome and that common genetic variation in GTF2I mediates oxytocin reactivity, and its correlates, in healthy populations. Third, we describe findings relevant to the hypothesis that the GTF2I gene is subject to parent of origin effects whose behavioral expression fits with predictions from the kinship theory of genomic imprinting. Fourth, we describe how Williams syndrome can be considered, in part, as an autistic syndrome of Lorna Wing's 'active-but-odd' autism subtype, in contrast to associations of duplications with both schizophrenia and autism. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

DEFF Research Database (Denmark)

Mehta, Divya; Tropf, Felix C; Gratten, Jacob

2016-01-01

IMPORTANCE: A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due......), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. CONCLUSIONS AND RELEVANCE: This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported...

GABBR1 has a HERV-W LTR in its regulatory region – a possible implication for schizophrenia

Directory of Open Access Journals (Sweden)

Hegyi Hedi

2013-02-01

Full Text Available Abstract Schizophrenia is a complex disease with uncertain aetiology. We suggest GABBR1, GABA receptor B1 implicated in schizophrenia based on a HERV-W LTR in the regulatory region of GABBR1. Our hypothesis is supported by: (i GABBR1 is in the 6p22 genomic region most often implicated in schizophrenia; (ii microarray studies found that only presynaptic pathway-related genes, including GABA receptors, have altered expression in schizophrenic patients and (iii it explains how HERV-W elements, expressed in schizophrenia, play a role in the disease: by altering the expression of GABBR1 via a long terminal repeat that is also a regulatory element to GABBR1. Reviewers This paper was reviewed by Sandor Pongor and Martijn Huynen.

Schizophrenia: What's Arc Got to Do with It?

Science.gov (United States)

Managò, Francesca; Papaleo, Francesco

2017-01-01

Human studies of schizophrenia are now reporting a previously unidentified genetic convergence on postsynaptic signaling complexes such as the activity-regulated cytoskeletal-associated (Arc) gene. However, because this evidence is still very recent, the neurobiological implication of Arc in schizophrenia is still scattered and unrecognized. Here, we first review current and developing findings connecting Arc in schizophrenia. We then highlight recent and previous findings from preclinical mouse models that elucidate how Arc genetic modifications might recapitulate schizophrenia-relevant behavioral phenotypes following the novel Research Domain Criteria (RDoC) framework. Building on this, we finally compare and evaluate several lines of evidence demonstrating that Arc genetics can alter both glutamatergic and dopaminergic systems in a very selective way, again consistent with molecular alterations characteristic of schizophrenia. Despite being only initial, accumulating and compelling data are showing that Arc might be one of the primary biological players in schizophrenia. Synaptic plasticity alterations in the genetic architecture of psychiatric disorders might be a rule, not an exception. Thus, we anticipate that additional evidence will soon emerge to clarify the Arc-dependent mechanisms involved in the psychiatric-related dysfunctional behavior.

California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS)

OpenAIRE

Stone, WS; Mesholam-Gately, RI; Braff, DL; Calkins, ME; Freedman, R; Green, MF; Greenwood, TA; Gur, RE; Gur, RCC; Lazzeroni, LC; Light, GA; Nuechterlein, KH; Olincy, A; Radant, AD; Siever, LJ

2014-01-01

© 2014. The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded “milder“ SZ phenotypes than those acquired subsequently in the COGS-2 case-control de...

California verbal learning test-ii performance in schizophrenia as a function of ascertainment strategy: Comparing the first and second phases of the consortium on the genetics of schizophrenia (COGS)

OpenAIRE

Stone, WS; Mesholam-Gately, RI; Braff, DL; Calkins, ME; Freedman, R; Green, MF; Greenwood, TA; Gur, RE; Gur, RC; Lazzeroni, LC; Light, GA; Nuechterlein, KH; Olincy, A; Radant, AD; Siever, LJ

2015-01-01

© 2014. The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control de...

Verbal working memory in schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) study: the moderating role of smoking status and antipsychotic medications.

Science.gov (United States)

Lee, Junghee; Green, Michael F; Calkins, Monica E; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Light, Gregory A; Nuechterlein, Keith H; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2015-04-01

Working memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. From 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter-number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. Schizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. Results confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke. Copyright © 2014 Elsevier B.V. All rights reserved.

Genetic susceptibility to radiations. Which impact on medical practice

International Nuclear Information System (INIS)

Alapetite, C.; Cosset, J. M.; Bourguignon, M. H.; Masse, R.

2000-01-01

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiation. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiation for better treatment of their malignant tumors. Although only a small percentage of individuals are hypersensitive to radiation effects, all medical specialists using ionising radiation should be aware of this new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes ...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiation. Then the main tests capable of detecting in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for this specific subset of patients suffering from a genetic disorder with a susceptibility to radiation

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

Science.gov (United States)

Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

2015-09-01

Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. © 2015 American Heart Association, Inc.

Behavioural Susceptibility Theory: Professor Jane Wardle and the Role of Appetite in Genetic Risk of Obesity.

Science.gov (United States)

Llewellyn, Clare H; Fildes, Alison

2017-03-01

There is considerable variability in human body weight, despite the ubiquity of the 'obesogenic' environment. Human body weight has a strong genetic basis and it has been hypothesised that genetic susceptibility to the environment explains variation in human body weight, with differences in appetite being implicated as the mediating mechanism; so-called 'behavioural susceptibility theory' (BST), first described by Professor Jane Wardle. This review summarises the evidence for the role of appetite as a mediator of genetic risk of obesity. Variation in appetitive traits is observable from infancy, drives early weight gain and is highly heritable in infancy and childhood. Obesity-related common genetic variants identified through genome-wide association studies show associations with appetitive traits, and appetite mediates part of the observed association between genetic risk and adiposity. Obesity results from an interaction between genetic susceptibility to overeating and exposure to an 'obesogenic' food environment.

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population.

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Mai-Juan Ma

Full Text Available BACKGROUND: Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk. PRINCIPAL FINDINGS: To specifically investigated whether single nucleotide polymorphisms (SNPs in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726 was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32-2.05, p(corrected = 9.27E-5 increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T were also associated with susceptibility to pulmonary tuberculosis (p(corrected = 0.0001 and 0.029, respectively. CONCLUSIONS: Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.

Neuregulin-1 genotypes and eye movements in schizophrenia

DEFF Research Database (Denmark)

Haraldsson, H.M.; Ettinger, U.; Magnusdottir, B.B.

2010-01-01

Neuregulin-1 (NRG-1) is a putative susceptibility gene for schizophrenia but the neurocognitive processes that may involve NRG-1 in schizophrenia are unknown. Deficits in antisaccade (AS) and smooth pursuit eye movements (SPEM) are promising endophenotypes, which may be associated with brain...... dysfunctions underlying the pathophysiology of schizophrenia. The aim of this study was to investigate the associations of NRG-1 genotypes with AS and SPEM in schizophrenia patients and healthy controls. Patients (N = 113) and controls (N = 106) were genotyped for two NRG-1 single nucleotide polymorphisms...... findings of impaired AS and SPEM performance in schizophrenia patients (all P

Regional brain activity during early visual perception in unaffected siblings of schizophrenia patients.

Science.gov (United States)

Lee, Junghee; Cohen, Mark S; Engel, Stephen A; Glahn, David; Nuechterlein, Keith H; Wynn, Jonathan K; Green, Michael F

2010-07-01

Visual masking paradigms assess the early part of visual information processing, which may reflect vulnerability measures for schizophrenia. We examined the neural substrates of visual backward performance in unaffected sibling of schizophrenia patients using functional magnetic resonance imaging (fMRI). Twenty-one unaffected siblings of schizophrenia patients and 19 healthy controls performed a backward masking task and three functional localizer tasks to identify three visual processing regions of interest (ROI): lateral occipital complex (LO), the motion-sensitive area, and retinotopic areas. In the masking task, we systematically manipulated stimulus onset asynchronies (SOAs). We analyzed fMRI data in two complementary ways: 1) an ROI approach for three visual areas, and 2) a whole-brain analysis. The groups did not differ in behavioral performance. For ROI analysis, both groups increased activation as SOAs increased in LO. Groups did not differ in activation levels of the three ROIs. For whole-brain analysis, controls increased activation as a function of SOAs, compared with siblings in several regions (i.e., anterior cingulate cortex, posterior cingulate cortex, inferior prefrontal cortex, inferior parietal lobule). The study found: 1) area LO showed sensitivity to the masking effect in both groups; 2) siblings did not differ from controls in activation of LO; and 3) groups differed significantly in several brain regions outside visual processing areas that have been related to attentional or re-entrant processes. These findings suggest that LO dysfunction may be a disease indicator rather than a risk indicator for schizophrenia. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Potential Value of Genomic Copy Number Variations in Schizophrenia

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Chuanjun Zhuo

2017-06-01

Full Text Available Schizophrenia is a devastating neuropsychiatric disorder affecting approximately 1% of the global population, and the disease has imposed a considerable burden on families and society. Although, the exact cause of schizophrenia remains unknown, several lines of scientific evidence have revealed that genetic variants are strongly correlated with the development and early onset of the disease. In fact, the heritability among patients suffering from schizophrenia is as high as 80%. Genomic copy number variations (CNVs are one of the main forms of genomic variations, ubiquitously occurring in the human genome. An increasing number of studies have shown that CNVs account for population diversity and genetically related diseases, including schizophrenia. The last decade has witnessed rapid advances in the development of novel genomic technologies, which have led to the identification of schizophrenia-associated CNVs, insight into the roles of the affected genes in their intervals in schizophrenia, and successful manipulation of the target CNVs. In this review, we focus on the recent discoveries of important CNVs that are associated with schizophrenia and outline the potential values that the study of CNVs will bring to the areas of schizophrenia research, diagnosis, and therapy. Furthermore, with the help of the novel genetic tool known as the Clustered Regularly Interspaced Short Palindromic Repeats-associated nuclease 9 (CRISPR/Cas9 system, the pathogenic CNVs as genomic defects could be corrected. In conclusion, the recent novel findings of schizophrenia-associated CNVs offer an exciting opportunity for schizophrenia research to decipher the pathological mechanisms underlying the onset and development of schizophrenia as well as to provide potential clinical applications in genetic counseling, diagnosis, and therapy for this complex mental disease.

Brain expressed microRNAs implicated in schizophrenia etiology

DEFF Research Database (Denmark)

Hansen, Thomas; Olsen, Line; Lindow, Morten

2007-01-01

Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors...

Genome-Wide Supported Risk Variants in MIR137, CACNA1C, CSMD1, DRD2, and GRM3 Contribute to Schizophrenia Susceptibility in Pakistani Population.

Science.gov (United States)

Fatima, Ambrin; Farooq, Muhammad; Abdullah, Uzma; Tariq, Muhammad; Mustafa, Tanveer; Iqbal, Muhammad; Tommerup, Niels; Mahmood Baig, Shahid

2017-09-01

Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. Recently, MIR137 , CACNA1C , CSMD1 , DRD2 , and GRM3 have been reported as the most robustly emerging candidates involved in the etiology of schizophrenia. In this case control study, we performed an association analysis of rs1625579 ( MIR137 ), rs1006737, rs4765905 ( CACNA1C ), rs10503253 ( CSMD1 ), rs1076560 ( DRD2 ), rs12704290, rs6465084, and rs148754219 ( GRM3 ) in Pakistani population. Schizophrenia was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV). Detailed clinical information, family history of all patients and healthy controls were collected. RFLP based case control association study was performed in a Pakistani cohort of 508 schizophrenia patients and 300 healthy control subjects. Alleles and genotype frequencies were calculated using SPSS. A significant difference in the genotype and allele frequencies for rs4765905, rs1076560 and rs6465084 were found between the patients and controls (p=0.000). This study provides substantial evidence supporting the role of CACNA1C , GRM3 and DRD2 as schizophrenia susceptibility genes in Pakistani population.

Genetic diversity and in vitro antibiotic susceptibility profile of ...

African Journals Online (AJOL)

We assessed the genetic diversity of forty Salmonella isolates obtained from selected domestic water and waste water sources in the Eastern Cape Province of South Africa using DNA fingerprinting and antibiotic susceptibility profile as test indices. Restriction digests and SDS/PAGE as well as the DNA dendograms of the ...

Canine susceptibility to visceral leishmaniasis: A systematic review upon genetic aspects, considering breed factors and immunological concepts.

Science.gov (United States)

de Vasconcelos, Tassia Cristina Bello; Furtado, Marina Carvalho; Belo, Vínicus Silva; Morgado, Fernanda Nazaré; Figueiredo, Fabiano Borges

2017-10-05

Dogs have different susceptibility degrees to leishmaniasis; however, genetic research on this theme is scarce, manly on visceral form. The aims of this systematic review were to describe and discuss the existing scientific findings on genetic susceptibility to canine leishmaniasis, as well as to show the gaps of the existing knowledge. Twelve articles were selected, including breed immunological studies, genome wide associations or other gene polymorphism or gene sequencing studies, and transcription approaches. As main results of literature, there was a suggestion of genetic clinical resistance background for Ibizan Hound dogs, and alleles associated with protection or susceptibility to visceral leishmaniasis in Boxer dogs. Genetic markers can explain phenotypic variance in both pro- and anti-inflammatory cytokines and in cellular immune responses, including antigen presentation. Many gene segments are involved in canine visceral leishmaniasis phenotype, with Natural Resistance Associated Macrophage Protein 1 (NRAMP1) as the most studied. This was related to both protection and susceptibility. In comparison with murine and human genetic approaches, lack of knowledge in dogs is notorious, with many possibilities for new studies, revealing a wide field to be assessed on canine leishmaniasis susceptibility research. Copyright © 2017 Elsevier B.V. All rights reserved.

Identifying Gene-Environment Interactions in Schizophrenia

DEFF Research Database (Denmark)

van Os, Jim; Rutten, Bart P; Myin-Germeys, Inez

2014-01-01

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual...... of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap...

Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa

Science.gov (United States)

Tosh, Kerrie; Campbell, Sarah J.; Fielding, Katherine; Sillah, Jackson; Bah, Boubacar; Gustafson, Per; Manneh, Kebba; Lisse, Ida; Sirugo, Giorgio; Bennett, Steve; Aaby, Peter; McAdam, Keith P. W. J.; Bah-Sow, Oumou; Lienhardt, Christian; Kramnik, Igor; Hill, Adrian V. S.

2006-01-01

The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans. PMID:16803959

Ethical issues of genetic susceptibility testing for occupational diseases: opinions of trainees in a high-risk job

NARCIS (Netherlands)

Visser, M. J.; Rhebergen, M. D. F.; Kezic, S.; van Dijk, F. J. H.; Willems, D. L.; Verberk, M. M.

2013-01-01

Genetic research has opened up possibilities for identification of persons with an increased susceptibility for occupational disease. However, regulations considering the ethical issues that are inevitably associated with the use of genetic tests for susceptibility for occupational diseases are

Search for common haplotypes on chromosome 22q in patients with schizophrenia or bipolar disorder from the Faroe Islands

DEFF Research Database (Denmark)

Jorgensen, Tove H; Børglum, A.D; Mors, O

2002-01-01

Chromosome 22q may harbor risk genes for schizophrenia and bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. Patients with schizophrenia and bipolar affective disorder from the Faroe...... was found at a segment of at least 1.1 cM including markers D22S1161 and D22S922 (P=0.0081 in the test for association). Our results also support the a priori evidence of a susceptibility gene to schizophrenia at a segment of at least 0.45 cM including markers D22S279 and D22S276 (P=0.0075). Patients were...... tested for the presence of a missense mutation in the WKL1 gene encoding a putative cation channel close to segment D22S1161-D22S922, which has been associated with schizophrenia. We did not find this mutation in schizophrenic or bipolar patients or the controls from the Faroe Islands. © 2002 Wiley...

Brief Report: No Association between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

Science.gov (United States)

Schirmbeck, Frederike; Georgi, Alexander; Strohmaier, Jana; Schmael, Christine; Boesshenz, Katja V.; Muhleisen, Thomas W.; Herms, Stefan; Hoffmann, Per; Jamra, Rami Abou; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Nothen, Markus M.; Cichon, Sven; Rietschel, Marcella; Schulze, Thomas G.

2008-01-01

Whereas "Dysbindin" is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. ("J Autism Dev…

Identification of Genetic Susceptibility to Childhood Cancer through Analysis of Genes in Parallel

Science.gov (United States)

Plon, Sharon E.; Wheeler, David A.; Strong, Louise C.; Tomlinson, Gail E.; Pirics, Michael; Meng, Qingchang; Cheung, Hannah C.; Begin, Phyllis R.; Muzny, Donna M.; Lewis, Lora; Biegel, Jaclyn A.; Gibbs, Richard A.

2011-01-01

Clinical cancer genetic susceptibility analysis typically proceeds sequentially beginning with the most likely causative gene. The process is time consuming and the yield is low particularly for families with unusual patterns of cancer. We determined the results of in parallel mutation analysis of a large cancer-associated gene panel. We performed deletion analysis and sequenced the coding regions of 45 genes (8 oncogenes and 37 tumor suppressor or DNA repair genes) in 48 childhood cancer patients who also (1) were diagnosed with a second malignancy under age 30, (2) have a sibling diagnosed with cancer under age 30 and/or (3) have a major congenital anomaly or developmental delay. Deleterious mutations were identified in 6 of 48 (13%) families, 4 of which met the sibling criteria. Mutations were identified in genes previously implicated in both dominant and recessive childhood syndromes including SMARCB1, PMS2, and TP53. No pathogenic deletions were identified. This approach has provided efficient identification of childhood cancer susceptibility mutations and will have greater utility as additional cancer susceptibility genes are identified. Integrating parallel analysis of large gene panels into clinical testing will speed results and increase diagnostic yield. The failure to detect mutations in 87% of families highlights that a number of childhood cancer susceptibility genes remain to be discovered. PMID:21356188

Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: A novel candidate SNP approach

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Daniel Ian Jacobs

2012-10-01

Full Text Available Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. Methods: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. Conclusions: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

Assessing the risk for suicide in schizophrenia according to migration, ethnicity and geographical ancestry.

Science.gov (United States)

Hettige, Nuwan C; Bani-Fatemi, Ali; Kennedy, James L; De Luca, Vincenzo

2017-02-09

Suicide is a leading cause of mortality among those afflicted by schizophrenia. Previous studies demonstrated that the stressors associated with immigration may lead to an onset of schizophrenia and suicide separately in susceptible individuals. However, no studies have shown whether immigration may lead to suicidal behaviour for individuals with schizophrenia. Our study proposes that an individual's geographical ancestry, ethnicity or migration status may be predictive of suicide risk in schizophrenia. In a sample of 276 participants with schizophrenia spectrum disorders, we conducted cross-sectional assessments to collect clinical information. Self-identified ethnicity and suicide history were collected through self-report questionnaires and interview-based scales. Ancestry was identified using 292 genetic markers from HapMap. Migrants were classified as those who immigrated to Canada during their lifetime. Using a regression analysis, we tested whether a history of migration, ethnicity or geographical ancestry were predictive of a history of suicide attempts. Our analysis failed to demonstrate a significant relationship between suicide history and migration, ethnicity or ancestry. However, ethnicity appears to be significantly associated with the number of psychiatric hospitalizations in our sample. Ethnicity and migration history are not predictive of previous suicide attempts. Ethnicity may be an important demographic factor affecting access to mental health resources and frequency of hospitalizations.

Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

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Tariq Waseem Chohan

2014-09-01

Full Text Available Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1 and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET and wild-type (WT mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV and the dentate gyrus (DG of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex.

Study of a possible role of the monoamine oxidase A (MAOA) gene in paranoid schizophrenia among a Chinese population.

Science.gov (United States)

Sun, Yuhui; Zhang, Jiexu; Yuan, Yanbo; Yu, Xin; Shen, Yan; Xu, Qi

2012-01-01

Monoamine oxidase A (MAOA) is the enzyme responsible for degradation of several monoamines, such as dopamine and serotonin that are considered as being two of the most important neurotransmitters involved in the pathophysiology of schizophrenia. To study a possible role of the MAOA gene in conferring susceptibility to schizophrenia, the present study genotyped the variable number of tandem repeat (VNTR) polymorphism and 41 SNPs across this gene among 555 unrelated patients with paranoid schizophrenia and 567 unrelated healthy controls. Quantitative real-time PCR analysis was employed to quantify expression of MAOA mRNA in 73 drug-free patients. While none of these genotyped DNA markers showed allelic association with paranoid schizophrenia, haplotypic association was found for the VNTR-rs6323, VNTR-rs1137070, and VNTR-rs6323-rs1137070 haplotypes in female subjects. Nevertheless, no significant change of the expression of MAOA mRNA was detected in either female or male patients with paranoid schizophrenia. Our study suggests that the interaction between genetic variants within the MAOA gene may contribute to an increased risk of paranoid schizophrenia, but the precise mechanism needs further investigation. Copyright © 2011 Wiley Periodicals, Inc.

GWAS, Cytomegalovirus Infection, and Schizophrenia

DEFF Research Database (Denmark)

Grove, Jakob; Børglum, Anders; Pearce, Brad D

2014-01-01

In recent years, good progress has been made in uncovering the genetic underpinnings of schizophrenia. Even so, as a polygenic disorder, schizophrenia has a complex etiology that is far from understood. Meanwhile, data are being collected enabling the study of interactions between genes...... and the environment. A confluence of data from genetic and environmental exposure studies point to the role of infections and immunity in the pathophysiology of schizophrenia. In a recent study by Børglum et al., a single nucleotide polymorphism (SNP) in the gene CTNNA3 was identified that may provide clues to gene......-environment interactions. The carriers of the minor allele for the SNP had a fivefold risk of later developing schizophrenia if their mothers were CMV positive, while the children not carrying the allele had no excess risk from maternal CMV. In the current paper, we summarize recent advances to clarify a possible...

SNP8NRG433E1006 NEUREGULIN-1 GENETIC VARIATION IN BATAKS ETHNIC WITH SCHIZOPHRENIA PARANOID AND HEALTHY CONTROL

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Elmeida Effendy

2014-05-01

Full Text Available The neuregulin 1 (NRG1 gene which influences the development of white matter connectivity has been associated with schizophrenia. It influences neuronal migration, synaptogenesis, gliogenesis, neuron-glia communication, myelination, and neurotransmission in the brain and others. NRG1 is located in 8p13, and it is frequently replicated in schizphrenia. SNP8NRG433E1006 gene NRG1 is one of core at risk haplotype of schizphrenia. This study looked forward differences SNP8NRG433E1006 neuregulin 1 between Bataks ethnic with schizophrenia paranoid and Bataks ethnic healthy control. Methods: Batak ethnic with schizophrenia paranoid were recruited and interviewed with semi-structured MINI ICD-X to establish the diagnosis. All the eligible subjects were requested their permission for blood sampling. Healthy Batak ethnic were also recruited by mathcing the age and gender. The blood samples went through DNA isolation, Nested PCR, and DNA sequencing. Results: Ninety three subjects were recruited, but only 74 blood samples were succesfully sequenced. We found three types of polymorphisms, i.e. G/A allele at base pair (bp 76, G/T allele at bp 112, and deletion at bp 110 in Batak ethnic with schizophrenia. There were two kind sequences at bp 113-116 in Batak ethnics, and Batak ethnics with ATCG were at higher risk for having schizophrenia. This study support that NRG1 is a schizophrenia-susceptibility gene.

Genetic susceptibility to radiation: which impact on medical practice?

Energy Technology Data Exchange (ETDEWEB)

Alapetite, C.; Cosset, J.M. [Institut Curie, Dept. de Radiotherapie, 75 - Paris (France); Bourguignon, M.H.; Masse, R. [Office de Protection contre les Rayonnements Ionisants, 78 - le Vesinet (France)

2001-07-01

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiations. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiations for a better cure of their malignant tumors. Although only a small percentage of individuals are 'hypersensitive' to radiation effects, all medical specialists using ionising radiations should be aware of these new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiations. Then the main tests capable to detect in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for these specific subset of patients suffering from a genetic disorder with a susceptibility to radiations. (author)

Genetic susceptibility to radiation: which impact on medical practice?

International Nuclear Information System (INIS)

Alapetite, C.; Cosset, J.M.; Bourguignon, M.H.; Masse, R.

2001-01-01

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiations. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiations for a better cure of their malignant tumors. Although only a small percentage of individuals are 'hypersensitive' to radiation effects, all medical specialists using ionising radiations should be aware of these new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiations. Then the main tests capable to detect in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for these specific subset of patients suffering from a genetic disorder with a susceptibility to radiations. (author)

Genetic control of susceptibility to apoptosis of thymocytes

International Nuclear Information System (INIS)

Mori, N.; Okumoto, M.; Morimoto, J.; Imai, S.; Matsuyama, T.; Takamori, Y.; Yagasaki, O.

1992-01-01

Genetic control of the susceptibility of thymocytes to radiation-induced apoptosis in mice was investigated by counting dead cells in a selected area of thymic cortex on histological specimens after whole-body X-irradiation. The number of dead cells increased almost linearly with doses in BALB/cHeA and STS/A mice. However, dead cell counts in BALB/cHeA mice were more than twice those in STS/A mice at each dose. C57BL/6N and B10.BR mice exhibited a sensitive phenotype similar to BALB/cHeA mice, while C3H/HeMsNrs and NFS/N mice showed a resistant phenotype similar to STS/A mice. Sex difference in the susceptibility of thymocytes to cell death was not recognized in BALB/cHeA and STS/A mice. Resistance was dominant over susceptibility in the progenies of reciprocal crosses between the two strains, indicating an autosomal inheritance. The segregation ratio of susceptible to resistant phenotype in the backcrosses of (BALB/cHeA X STS/A)F 1 with BALB/cHeA was not significantly different from 1 : 1 and all backcrosses of (BALB/cHeA X STS/A)F 1 with STS/A exhibited a resistant phenotype. The results demonstrated that the difference in the susceptibility of thymocytes to radiation-induced apoptosis in the two strains of mice is due to one major autosomal allele. (author)

A Hybrid Machine Learning Method for Fusing fMRI and Genetic Data: Combining both Improves Classification of Schizophrenia

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Honghui Yang

2010-10-01

Full Text Available We demonstrate a hybrid machine learning method to classify schizophrenia patients and healthy controls, using functional magnetic resonance imaging (fMRI and single nucleotide polymorphism (SNP data. The method consists of four stages: (1 SNPs with the most discriminating information between the healthy controls and schizophrenia patients are selected to construct a support vector machine ensemble (SNP-SVME. (2 Voxels in the fMRI map contributing to classification are selected to build another SVME (Voxel-SVME. (3 Components of fMRI activation obtained with independent component analysis (ICA are used to construct a single SVM classifier (ICA-SVMC. (4 The above three models are combined into a single module using a majority voting approach to make a final decision (Combined SNP-fMRI. The method was evaluated by a fully-validated leave-one-out method using 40 subjects (20 patients and 20 controls. The classification accuracy was: 0.74 for SNP-SVME, 0.82 for Voxel-SVME, 0.83 for ICA-SVMC, and 0.87 for Combined SNP-fMRI. Experimental results show that better classification accuracy was achieved by combining genetic and fMRI data than using either alone, indicating that genetic and brain function representing different, but partially complementary aspects, of schizophrenia etiopathology. This study suggests an effective way to reassess biological classification of individuals with schizophrenia, which is also potentially useful for identifying diagnostically important markers for the disorder.

Researchers Find a Mechanism for Schizophrenia

Science.gov (United States)

... issue Health Capsule Researchers Find a Mechanism for Schizophrenia En español Send us your comments Scientists uncovered a mechanism behind genetic variations previously linked to schizophrenia. The findings may lead to new clinical approaches. ...

A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure.

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Shanshan Zhou

2017-07-01

Full Text Available The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.

22q11.2 deletion carriers and schizophrenia-associated novel variants.

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Balan, S; Iwayama, Y; Toyota, T; Toyoshima, M; Maekawa, M; Yoshikawa, T

2014-01-01

The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia.

Neuregulin 1: a prime candidate for research into gene-environment interactions in schizophrenia? Insights from genetic rodent models

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Tim eKarl

2013-08-01

Full Text Available Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the ‘two-hit hypothesis’ of schizophrenia predicting that genetic and environmental risk factors (GxE interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1 with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g. transmembrane domain Nrg1, Type II Nrg1, which have been exposed to different forms of stress (acute versus chronic, restraint versus social and housing conditions (standard laboratory versus minimally enriched housing. These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms.

Recent advances in understanding schizophrenia.

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Haller, Chiara S; Padmanabhan, Jaya L; Lizano, Paulo; Torous, John; Keshavan, Matcheri

2014-01-01

Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia. This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work

Refined candidate region specified by haplotype sharing for Escherichia coli F4ab/F4ac susceptibility alleles in pigs

DEFF Research Database (Denmark)

Jacobsen, Mette Juul; Kracht, Steffen Skaarup; Esteso, G.

2009-01-01

Infection of the small intestine by enterotoxigenic Escherichia coli F4ab/ac is a major welfare problem and financial burden for the pig industry. Natural resistance to this infection is inherited as a Mendelian recessive trait, and a polymorphism in the MUC4 gene segregating for susceptibility....../resistance is presently used in a selection programme by the Danish pig breeding industry. To elucidate the genetic background involved in E. coli F4ab/ac susceptibility in pigs, a detailed haplotype map of the porcine candidate region was established. This region covers approximately 3.7 Mb. The material used...... for the study is a three generation family, where the founders are two Wild boars and eight Large White sows. All pigs have been phenotyped for susceptibility to F4ab/ac using an adhesion assay. Their haplotypes are known from segregation analysis using flanking markes. By a targeted approach, the candidate...

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene

DEFF Research Database (Denmark)

Tosic, Mirjana; Ott, Jurg; Barral, Sandra

2006-01-01

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCLM......) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia....

Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene

DEFF Research Database (Denmark)

Tosic, Mirjana; Ott, Jurg; Barral, Sandra

2006-01-01

Oxidative stress could be involved in the pathophysiology of schizophrenia, a major psychiatric disorder. Glutathione (GSH), a redox regulator, is decreased in patients' cerebrospinal fluid and prefrontal cortex. The gene of the key GSH-synthesizing enzyme, glutamate cysteine ligase modifier (GCL......) subunit, is strongly associated with schizophrenia in two case-control studies and in one family study. GCLM gene expression is decreased in patients' fibroblasts. Thus, GSH metabolism dysfunction is proposed as one of the vulnerability factors for schizophrenia....

Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.

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Hida, Hirotake; Mouri, Akihiro; Noda, Yukihiro

2013-01-01

Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.

Next-generation sequencing in schizophrenia and other neuropsychiatric disorders.

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Schreiber, Matthew; Dorschner, Michael; Tsuang, Debby

2013-10-01

Schizophrenia is a debilitating lifelong illness that lacks a cure and poses a worldwide public health burden. The disease is characterized by a heterogeneous clinical and genetic presentation that complicates research efforts to identify causative genetic variations. This review examines the potential of current findings in schizophrenia and in other related neuropsychiatric disorders for application in next-generation technologies, particularly whole-exome sequencing (WES) and whole-genome sequencing (WGS). These approaches may lead to the discovery of underlying genetic factors for schizophrenia and may thereby identify and target novel therapeutic targets for this devastating disorder. © 2013 Wiley Periodicals, Inc.

Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies

Science.gov (United States)

Joon, Aron; Brewster, Abenaa M.; Chen, Wei V.; Eng, Cathy; Shete, Sanjay; Casey, Graham; Schumacher, Fredrick; Lin, Yi; Harrison, Tabitha A.; White, Emily; Ahsan, Habibul; Andrulis, Irene L.; Whittemore, Alice S.; Ko Win, Aung; Schmidt, Daniel F.; Kapuscinski, Miroslaw K.; Ochs-Balcom, Heather M.; Gallinger, Steven; Jenkins, Mark A.; Newcomb, Polly A.; Lindor, Noralane M.; Peters, Ulrike; Amos, Christopher I.; Lynch, Patrick M.

2018-01-01

Background Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. Methods To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second-degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at Pcolorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E-04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). Conclusion The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation. PMID:29698419

MicroRNA Dysregulation, Gene Networks, and Risk for Schizophrenia in 22q11.2 Deletion Syndrome

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Merico, Daniele; Costain, Gregory; Butcher, Nancy J.; Warnica, William; Ogura, Lucas; Alfred, Simon E.; Brzustowicz, Linda M.; Bassett, Anne S.

2014-01-01

The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways. PMID:25484875

Association of the IFN-γ (+874A/T) Genetic Polymorphism with Paranoid Schizophrenia in Tunisian Population.

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Jemli, Achraf; Eshili, Awatef; Trifa, Fatma; Mechri, Anouar; Zaafrane, Ferid; Gaha, Lotfi; Juckel, George; Tensaout, Besma Bel Hadj Jrad

2017-02-01

Since growing evidence suggests a significant role of chronic low-grade inflammation in the physiopathology of schizophrenia, we have hypothesized that functional genetic variant of the IFN gamma (IFN-γ; +874A/T; rs2430561) gene may be involved in the predisposition to schizophrenia. This research is based on a case-control study which aims to identify whether polymorphism of the IFN-γ gene is a risk factor for the development of schizophrenia. The RFLP-PCR genotyping of the IFN-γ gene was conducted on a Tunisian population composed of 218 patients and 162 controls. The IFN-γ (+874A/T) polymorphism analysis showed higher frequencies of minor homozygous genotype (TT) and allele (T) in all patients compared with controls (11.5 vs. 4.9%; p = 0.03, OR = 2.64 and 30.7 vs. 24.1%, p = 0.04, OR = 1.4, respectively). This correlation was confirmed for male but not for female patients. Also, the T allele was significantly more common among patients with paranoid schizophrenia when compared with controls (25.8 vs. 4.9%, p = 0.0001; OR = 6.7). Using the binary regression analysis to eliminate confounding factors as age and sex, only this last association remained significant (p = 0.03; OR = 1.76, CI = 1.05-2.93). In conclusion, our results showed a significant association between +874A/T polymorphism of IFN-γ and paranoid schizophrenia, suggesting that this single nucleotide polymorphism (SNP) or another at proximity could predispose to paranoid schizophrenia. Since the minor allele of this polymorphism was correlated with an increased expression of their product, our study validates the hypothesis of excessive pro-inflammatory cytokine in the physiopathology of paranoid schizophrenia.

Awareness of Cancer Susceptibility Genetic Testing

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Mai, Phuong L.; Vadaparampil, Susan Thomas; Breen, Nancy; McNeel, Timothy S.; Wideroff, Louise; Graubard, Barry I.

2014-01-01

Background Genetic testing for several cancer susceptibility syndromes is clinically available; however, existing data suggest limited population awareness of such tests. Purpose To examine awareness regarding cancer genetic testing in the U.S. population aged ≥25 years in the 2000, 2005, and 2010 National Health Interview Surveys. Methods The weighted percentages of respondents aware of cancer genetic tests, and percent changes from 2000–2005 and 2005–2010, overall and by demographic, family history, and healthcare factors were calculated. Interactions were used to evaluate the patterns of change in awareness between 2005 and 2010 among subgroups within each factor. To evaluate associations with awareness in 2005 and 2010, percentages were adjusted for covariates using multiple logistic regression. The analysis was performed in 2012. Results Awareness decreased from 44.4% to 41.5% (pAwareness increased between 2005 and 2010 in most subgroups, particularly among individuals in the South (p-interaction=0.03) or with a usual place of care (p-interaction=0.01). In 2005 and 2010, awareness was positively associated with personal or family cancer history and high perceived cancer risk, and inversely associated with racial/ethnic minorities, age 25–39 or ≥60 years, male gender, lower education and income levels, public or no health insurance, and no provider contact in 12 months. Conclusions Despite improvement from 2005 to 2010, ≤50% of the U.S. adult population was aware of cancer genetic testing in 2010. Notably, disparities persist for racial/ethnic minorities and individuals with limited health care access or income. PMID:24745633

Psychosis among "healthy" siblings of schizophrenia patients

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Partonen Timo

2006-01-01

Full Text Available Abstract Background Schizophrenia aggregates in families and accurate diagnoses are essential for genetic studies of schizophrenia. In this study, we investigated whether siblings of patients with schizophrenia can be identified as free of any psychotic disorder using only register information. We also analyzed the emergence of psychotic disorders among siblings of patients with schizophrenia during seven to eleven years of follow-up. Methods A genetically homogenous population isolate in north-eastern Finland having 365 families with 446 patients with a diagnosis of schizophrenia was initially identified in 1991 using four nationwide registers. Between 1998 and 2002, 124 patients and 183 siblings in 110 families were contacted and interviewed using SCID-I, SCID-II and SANS. We also compared the frequency of mental disorders between siblings and a random population comparison group sample. Results Thirty (16% siblings received a diagnosis of psychotic disorder in the interview. 14 siblings had had psychotic symptoms already before 1991, while 16 developed psychotic symptoms during the follow-up. Over half of the siblings (n = 99, 54% had a lifetime diagnosis of any mental disorder in the interview. Conclusion Register information cannot be used to exclude psychotic disorders among siblings of patients with schizophrenia. The high rate of emergence of new psychotic disorders among initially healthy siblings should be taken into account in genetic analysis.

Association of Increased Prenatal Estrogen With Risk Factors for Schizophrenia

OpenAIRE

Brown, James S.

2010-01-01

The author previously described a theoretical cause of schizophrenia based on the effects of estrogenic endocrine disruption. In the current review, the author describes how increased estrogen during pregnancy increases susceptibility to certain viral infections associated with increased risk for schizophrenia. The review further discusses how prenatal estrogen exposure could explain associations of schizophrenia with autoimmune diseases, urban environments, and stress. Based on the associati...

Laterality and mental disorders in the postgenomic age--A closer look at schizophrenia and language lateralization.

Science.gov (United States)

Ocklenburg, Sebastian; Güntürkün, Onur; Hugdahl, Kenneth; Hirnstein, Marco

2015-12-01

Most people are right-handed and show left-hemispheric language lateralization, but a minority exhibits left-handedness and right-hemispheric language lateralization. This atypical laterality pattern is observed significantly more often in schizophrenia patients than in the general population, which led several authors to conclude that there is a genetic link between laterality and schizophrenia. It has even been suggested that a failure in the lateralization process, orchestrated by genes, could be the primary cause of schizophrenia. However, the molecular genetic evidence for a link between laterality and schizophrenia is weak. Recent genetic evidence indicates that schizophrenia is not a single disorder but a group of heritable disorders caused by different genotypic networks leading to distinct clinical symptoms. To uncover the link between schizophrenia and laterality we therefore suggest a paradigm shift where genetics are not mapped on schizophrenia as a whole but on discrete schizophrenia symptoms. In addition, we provide a critical evaluation of current theories on the genetic link between schizophrenia and brain asymmetry. Copyright © 2015 Elsevier Ltd. All rights reserved.

Predicting risk and the emergence of schizophrenia.

LENUS (Irish Health Repository)

Clarke, Mary C

2012-09-01

This article gives an overview of genetic and environmental risk factors for schizophrenia. The presence of certain molecular, biological, and psychosocial factors at certain points in the life span, has been linked to later development of schizophrenia. All need to be considered in the context of schizophrenia as a lifelong brain disorder. Research interest in schizophrenia is shifting to late childhood\\/early adolescence for screening and preventative measures. This article discusses those environmental risk factors for schizophrenia for which there is the largest evidence base.

Genetics of Cognitive Endophenotypes in Schizophrenia : a Family-Based Study

NARCIS (Netherlands)

Aukes, M.F.

2009-01-01

Schizophrenia is a highly heritable, though complex disease; multiple genes and environmental factors influence its development. Most of these genes have small effects on schizophrenia. Therefore, the localization and identification of genes for schizophrenia has been difficult. An alternative

DNA Methylation Analysis of BRD1 Promoter Regions and the Schizophrenia rs138880 Risk Allele.

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Mads Dyrvig

Full Text Available The bromodomain containing 1 gene, BRD1 is essential for embryogenesis and CNS development. It encodes a protein that participates in histone modifying complexes and thereby regulates the expression of a large number of genes. Genetic variants in the BRD1 locus show association with schizophrenia and bipolar disorder and risk alleles in the promoter region correlate with reduced BRD1 expression. Insights into the transcriptional regulation of BRD1 and the pathogenic mechanisms associated with BRD1 risk variants, however, remain sparse. By studying transcripts in human HeLa and SH-SY5Y cells we provide evidence for differences in relative expression of BRD1 transcripts with three alternative 5' UTRs (exon 1C, 1B, and 1A. We further show that expression of these transcript variants covaries negatively with DNA methylation proportions in their upstream promoter regions suggesting that promoter usage might be regulated by DNA methylation. In line with findings that the risk allele of the rs138880 SNP in the BRD1 promoter region correlates with reduced BRD1 expression, we find that it is also associated with moderate regional BRD1 promoter hypermethylation in both adipose tissue and blood. Importantly, we demonstrate by inspecting available DNA methylation and expression data that these regions undergo changes in methylation during fetal brain development and that differences in their methylation proportions in fetal compared to postnatal frontal cortex correlate significantly with BRD1 expression. These findings suggest that BRD1 may be dysregulated in both the developing and mature brain of risk allele carriers. Finally, we demonstrate that commonly used mood stabilizers Lithium, Valproate, and Carbamazepine affect the expression of BRD1 in SH-SY5Y cells. Altogether this study indicates a link between genetic risk and epigenetic dysregulation of BRD1 which raises interesting perspectives for targeting the mechanisms pharmacologically.

Comparative study of genetic influence on the susceptibility of exotic ...

African Journals Online (AJOL)

This study investigated comparatively the genetic influence on the susceptibility of exotic cockerels, pullets and broilers to natural infection with infectious bursal disease (IBD) virus in a flock of 150 seven-week-old exotic breed of chickens comprising of 50 Black Harco cockerels, 50 Black Harco pullets and 50 White ...

Downregulated kynurenine 3-monooxygenase gene expression and enzyme activity in schizophrenia and genetic association with schizophrenia endophenotypes.

Science.gov (United States)

Wonodi, Ikwunga; Stine, O Colin; Sathyasaikumar, Korrapati V; Roberts, Rosalinda C; Mitchell, Braxton D; Hong, L Elliot; Kajii, Yasushi; Thaker, Gunvant K; Schwarcz, Robert

2011-07-01

Kynurenic acid, a metabolite of the kynurenine pathway of tryptophan degradation, is an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors and modulates glutamate, dopamine, and acetylcholine signaling. Cortical kynurenic acid concentrations are elevated in the brain and cerebrospinal fluid of schizophrenia patients. The proximal cause may be an impairment of kynurenine 3-monooxygenase (KMO), a rate-limiting enzyme at the branching point of the kynurenine pathway. To examine KMO messenger RNA expression and KMO enzyme activity in postmortem tissue from the frontal eye field (FEF; Brodmann area 6) obtained from schizophrenia individuals compared with healthy control individuals and to explore the relationship between KMO single-nucleotide polymorphisms and schizophrenia oculomotor endophenotypes. Case-control postmortem and clinical study. Maryland Brain Collection, outpatient clinics. Postmortem specimens from schizophrenia patients (n = 32) and control donors (n = 32) and a clinical sample of schizophrenia patients (n = 248) and healthy controls (n = 228). Comparison of quantitative KMO messenger RNA expression and KMO enzyme activity in postmortem FEF tissue between schizophrenia patients and controls and association of KMO single-nucleotide polymorphisms with messenger RNA expression in postmortem FEF and schizophrenia and oculomotor endophenotypes (ie, smooth pursuit eye movements and oculomotor delayed response). In postmortem tissue, we found a significant and correlated reduction in KMO gene expression and KMO enzyme activity in the FEF in schizophrenia patients. In the clinical sample, KMO rs2275163 was not associated with a diagnosis of schizophrenia but showed modest effects on predictive pursuit and visuospatial working memory endophenotypes. Our results provide converging lines of evidence implicating reduced KMO activity in the etiopathophysiology of schizophrenia and related neurocognitive deficits.

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

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Børglum, A D; Demontis, D; Grove, J; Pallesen, J; Hollegaard, M V; Pedersen, C B; Hedemand, A; Mattheisen, M; Uitterlinden, A; Nyegaard, M; Ørntoft, T; Wiuf, C; Didriksen, M; Nordentoft, M; Nöthen, M M; Rietschel, M; Ophoff, R A; Cichon, S; Yolken, R H; Hougaard, D M; Mortensen, P B; Mors, O

2014-03-01

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10(-6)) and rs8057927 in CDH13 (P=1.39 × 10(-5)). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10(-7)). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection was found for rs7902091 (P(SNP × CMV)=7.3 × 10(-7)) in CTNNA3, a gene not previously implicated in schizophrenia, stressing the importance of including environmental factors in genetic studies.

A framework for interpreting functional networks in schizophrenia

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Peter eWilliamson

2012-06-01

Full Text Available Some promising genetic correlates of schizophrenia have emerged in recent years but none explain more than a small fraction of cases. The challenge of our time is to characterize the neuronal networks underlying schizophrenia and other neuropsychiatric illnesses. It has been proposed that schizophrenia arises from a uniquely human brain network associated with directed effort including the dorsal anterior and posterior cingulate cortex, auditory cortex, and hippocampus and while mood disorders arise from a different brain network associated with emotional encoding including the ventral anterior cingulate cortex, orbital frontal cortex, and amygdala. Both interact with a representation network including the frontal and temporal poles and the fronto-insular cortex, allowing the representation of the thoughts, feelings and actions of self and others. This paper reviews recent morphological and functional literature in light of the proposed networks underlying these disorders. It is suggested that there is considerable support for the involvement of the directed effort network in schizophrenia from studies of brain structure with voxel-based morphometry (VBM and diffusion tensor imaging (DTI. While early studies of resting brain networks are inconclusive, functional magnetic resonance imaging imaging (fMRI studies of task-related networks clearly implicate these regions. In keeping with the model, functional deficits in regions associated with directed effort and self-monitoring are associated with structural anomalies in action-related regions in schizophrenic patients. VBM, DTI, fMRI studies of mood disordered patients support the involvement of a different network associated with emotional encoding. The distinction between disorders is enhanced by combining structural and functional data. It is concluded that brain networks associated with directed effort are particularly vulnerable to failure in the human brain leading to the symptoms of

Updating the mild encephalitis hypothesis of schizophrenia.

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Bechter, K

2013-04-05

Schizophrenia seems to be a heterogeneous disorder. Emerging evidence indicates that low level neuroinflammation (LLNI) may not occur infrequently. Many infectious agents with low overall pathogenicity are risk factors for psychoses including schizophrenia and for autoimmune disorders. According to the mild encephalitis (ME) hypothesis, LLNI represents the core pathogenetic mechanism in a schizophrenia subgroup that has syndromal overlap with other psychiatric disorders. ME may be triggered by infections, autoimmunity, toxicity, or trauma. A 'late hit' and gene-environment interaction are required to explain major findings about schizophrenia, and both aspects would be consistent with the ME hypothesis. Schizophrenia risk genes stay rather constant within populations despite a resulting low number of progeny; this may result from advantages associated with risk genes, e.g., an improved immune response, which may act protectively within changing environments, although they are associated with the disadvantage of increased susceptibility to psychotic disorders. Specific schizophrenic symptoms may arise with instances of LLNI when certain brain functional systems are involved, in addition to being shaped by pre-existing liability factors. Prodrome phase and the transition to a diseased status may be related to LLNI processes emerging and varying over time. The variability in the course of schizophrenia resembles the varying courses of autoimmune disorders, which result from three required factors: genes, the environment, and the immune system. Preliminary criteria for subgrouping neurodevelopmental, genetic, ME, and other types of schizophrenias are provided. A rare example of ME schizophrenia may be observed in Borna disease virus infection. Neurodevelopmental schizophrenia due to early infections has been estimated by others to explain approximately 30% of cases, but the underlying pathomechanisms of transition to disease remain in question. LLNI (e.g. from

Epidemiology and risk factors of schizophrenia.

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Janoutová, Jana; Janácková, Petra; Serý, Omar; Zeman, Tomás; Ambroz, Petr; Kovalová, Martina; Varechová, Katerina; Hosák, Ladislav; Jirík, Vitezslav; Janout, Vladimír

2016-01-01

Schizophrenia is a severe mental disorder that affects approximately one percent of the general population. The pathogenesis of schizophrenia is influenced by many risk factors, both environmental and genetic. The environmental factors include the date of birth, place of birth and seasonal effects, infectious diseases, complications during pregnancy and delivery, substance abuse and stress. At the present time, in addition to environmental factors, genetic factors are assumed to play a role in the development of the schizophrenia. The heritability of schizo- phrenia is up to 80%. If one parent suffers from the condition, the probability that it will be passed down to the offspring is 13%. If it is present in both parents, the risk is more than 20%. The opinions are varied as to the risk factors affecting the development of schizophrenia. Knowing these factors may greatly contribute to prevention of the condition.

Genes and environments in schizophrenia: The different pieces of a manifold puzzle.

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Réthelyi, János M; Benkovits, Judit; Bitter, István

2013-12-01

Genetic research targeting schizophrenia has undergone tremendous development during recent years. Supported by recently developed high-throughput genotyping technologies, both rare and common genetic variants have been identified that show consistent association with schizophrenia. These results have been replicated by independent studies and refined in meta-analyses. The genetic variation uncovered consists of common alleles, i.e. single nucleotide polymorphisms (SNPs) conveying small effects (odds ratios below 1.1) on disease risk. The source of rare variants is copy number variations (CNVs), only detectable in a small proportion of patients (3-5% for all known CNVs) with schizophrenia, furthermore extremely rare de novo mutations captured by next generation sequencing, the most recent technological advancement in the field. Despite these findings, the search for the genetic architecture underlying schizophrenia continues since these variants explain only a small proportion of the overall phenotypic variance. Gene-environment interactions provide a compelling model for resolving this paradox and interpreting the risk factors of schizophrenia. Epidemiologically proven risk factors, such as prenatal infection, obstetric complications, urbanicity, cannabis, and trauma have been demonstrated to interact with genetic risk, giving rise to higher prevalence rates or more severe symptomatology in individuals with direct or indirect genetic predisposition for schizophrenia. Further research will have to explain how the different forms of genetic variation interact and how environmental factors modulate their effects. Moreover, the challenging question lying ahead of us is how genetic and environmental factors translate to molecular disease pathways. New approaches, including animal studies and in vitro disease modeling, as well as innovative real-world environment assessment methods, will help to understand the complex etiology of schizophrenia. Copyright © 2013

Risk factors for development of schizophrenia

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Dunglová, Eva

2013-01-01

Schizophrenia is a severe disease. There is a complicity of genetic and environmental factors in schizophrenia onset. Factors with probable influence on development of schizophrenia are rate of urbanization, geographic location, migration, month of birth, maternal nutrition during pregnancy and birth complications, stress during pregnancy, length of lactation period, prenatal and postnatal infection exposure, exposure to a cat during childhood or cannabis abuse. Until now the information on t...

Developmental vitamin D deficiency and schizophrenia: the role of animal models.

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Schoenrock, S A; Tarantino, L M

2016-01-01

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D (DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia

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Ingason, A; Rujescu, D; Cichon, S

2011-01-01

.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion...... carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity...

Impaired glutathione synthesis in schizophrenia

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Gysin, René; Kraftsik, Rudolf; Sandell, Julie

2007-01-01

Schizophrenia is a complex multifactorial brain disorder with a genetic component. Convergent evidence has implicated oxidative stress and glutathione (GSH) deficits in the pathogenesis of this disease. The aim of the present study was to test whether schizophrenia is associated with a deficit...... of GSH synthesis. Cultured skin fibroblasts from schizophrenia patients and control subjects were challenged with oxidative stress, and parameters of the rate-limiting enzyme for the GSH synthesis, the glutamate cysteine ligase (GCL), were measured. Stressed cells of patients had a 26% (P = 0.......002) decreased GCL activity as compared with controls. This reduction correlated with a 29% (P schizophrenia in two...

Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review.

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Misiak, Błażej; Stramecki, Filip; Gawęda, Łukasz; Prochwicz, Katarzyna; Sąsiadek, Maria M; Moustafa, Ahmed A; Frydecka, Dorota

2017-08-18

Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD.

Biosocial characteristics of patients with paranoid schizophrenia

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Gergana K. Panayotova

2016-04-01

Full Text Available Schizophrenia is known as a complex disorder that combines both genetic and environmental factors. Different genes have been tested as candidates for association with schizophrenia and different environmental factors have been examined in many studies on epidemiology of schizophrenia. Specific environmental factors, such as nonspecific stress, mental and physical abuse, maternal diet during pregnancy, drug use, living in an urban setting, migration, seasonal effects on birth and exposure to infections, have been discussed as possible risk for schizophrenia. The present preliminary study is focused on the relations between biological and social characteristics of patients with paranoid schizophrenia with different cognitive levels, emotional and creative styles. Descriptive statistics, the Student's t-test and SPSS software, were used to analyse the relations mentioned. Differences between sexes and these concerning age of individuals (risk level of inheritance, ABO blood group distribution, triggering factors, aggressive behavior, single or multiple suicide attempts, levels of education and creative talents were indicated and discussed. The study identifies important trends and discuses essential biosocial relations in context of the knowledge for schizophrenia in Bulgaria. Future comparative investigations, including genetic markers and psychogenetic approaches, should be used in complex, in order to characterize the reasons for developing paranoid schizophrenia and the possible relations between biological, psychological and social factors better.

Association between catechol-O-methyltrasferase Val108/158Met genotype and prefrontal hemodynamic response in schizophrenia.

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Ryu Takizawa

Full Text Available BACKGROUND: "Imaging genetics" studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS. METHODOLOGY/PRINCIPAL FINDINGS: Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls. CONCLUSIONS/SIGNIFICANCE: These data suggest that the prefrontal NIRS signals can noninvasively detect the impact

Association between a genetic variant in the serotonin transporter gene (SLC6A4 and suicidal behavior in patients with schizophrenia

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Lindholm Carlström Eva

2012-05-01

Full Text Available Abstract Background The serotonin (5-hydroxytryptamin; 5-HT system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case–control sample. Methods Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9. Results We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted p-value 0.01, among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals. Conclusion The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.

Neurodevelopmental correlates in schizophrenia

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Ivković Maja

2003-01-01

Full Text Available Contemporary aetiopathogenetic considerations, based on neuro-imaging genetic and developmental neurobiology studies, suggest neurodevelopmental origin of schizophrenia. Several lines of evidence including structural abnormalities on in vivo brain imaging, the excess of prenatal and obstetric complications and the association of congenital and minor physical anomalies with schizophrenia, strongly indicate the neurodevelopmental pathogenesis of schizophrenia. On the other hand, controversial concept of psychotic continuum suggests schizophrenia and depression sharing the same genetic contribution to the pathogenesis. If this would be the case, depression could also be considered as neuro developmental disorder. The aims of the study were to investigate the association between: a pregnancy and birth complications (PBC, and b minor physical anomalies (MPA and schizophrenia or depression. Experimental groups consisted of 60 schizophrenic, 28 major depression patients and 30 healthy controls. All patients were diagnosed according to DSM-IV. Schizophrenic group was divided with regard to PANSS score into positive (n=32 and negative form (n=28 subgroups. PBC information were gathered from maternal recall while MPA were examined by using Waldrop scale for adults. The results showed that negative and positive schizophrenic subgroups had significantly more PBC than depressive group (p<0,05, as well than controls (p<0,001; p<0,05; respectively. There was no significant trend for more PBC in negative than in positive subgroup. All schizophrenic patients had higher rates of MPA than depressives (p<0,05. This trend for more MPA was not significant in comparison with healthy controls. These findings suggest that schizophrenia, especially its negative forms, could be considered as a member of the spectrum of neuro developmental disorders, which does not seem to be the case with depression. PBC and MPA could also be valuable in evaluation of risks for

The Schizophrenia-Associated BRD1 Gene Regulates Behavior, Neurotransmission, and Expression of Schizophrenia Risk Enriched Gene Sets in Mice.

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Qvist, Per; Christensen, Jane Hvarregaard; Vardya, Irina; Rajkumar, Anto Praveen; Mørk, Arne; Paternoster, Veerle; Füchtbauer, Ernst-Martin; Pallesen, Jonatan; Fryland, Tue; Dyrvig, Mads; Hauberg, Mads Engel; Lundsberg, Birgitte; Fejgin, Kim; Nyegaard, Mette; Jensen, Kimmo; Nyengaard, Jens Randel; Mors, Ole; Didriksen, Michael; Børglum, Anders Dupont

2017-07-01

The schizophrenia-associated BRD1 gene encodes a transcriptional regulator whose comprehensive chromatin interactome is enriched with schizophrenia risk genes. However, the biology underlying the disease association of BRD1 remains speculative. This study assessed the transcriptional drive of a schizophrenia-associated BRD1 risk variant in vitro. Accordingly, to examine the effects of reduced Brd1 expression, we generated a genetically modified Brd1 +/- mouse and subjected it to behavioral, electrophysiological, molecular, and integrative genomic analyses with focus on schizophrenia-relevant parameters. Brd1 +/- mice displayed cerebral histone H3K14 hypoacetylation and a broad range of behavioral changes with translational relevance to schizophrenia. These behaviors were accompanied by striatal dopamine/serotonin abnormalities and cortical excitation-inhibition imbalances involving loss of parvalbumin immunoreactive interneurons. RNA-sequencing analyses of cortical and striatal micropunches from Brd1 +/- and wild-type mice revealed differential expression of genes enriched for schizophrenia risk, including several schizophrenia genome-wide association study risk genes (e.g., calcium channel subunits [Cacna1c and Cacnb2], cholinergic muscarinic receptor 4 [Chrm4)], dopamine receptor D 2 [Drd2], and transcription factor 4 [Tcf4]). Integrative analyses further found differentially expressed genes to cluster in functional networks and canonical pathways associated with mental illness and molecular signaling processes (e.g., glutamatergic, monoaminergic, calcium, cyclic adenosine monophosphate [cAMP], dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa [DARPP-32], and cAMP responsive element binding protein signaling [CREB]). Our study bridges the gap between genetic association and pathogenic effects and yields novel insights into the unfolding molecular changes in the brain of a new schizophrenia model that incorporates genetic risk at three levels: allelic

Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

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Miguel eCalero

2015-04-01

Full Text Available Familial Alzheimer's disease (AD, mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2 involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4, the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

Prenatal Ontogeny as a Susceptibility Period for Cortical GABA Neuron Disturbances in Schizophrenia

OpenAIRE

Volk, David W.; Lewis, David A.

2013-01-01

Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex. Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny...

An in-depth characterization of the major psoriasis susceptibility locus identifies candidate susceptibility alleles within an HLA-C enhancer element.

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Alex Clop

Full Text Available Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC.

Effects of DISC1 Polymorphisms on Resting-State Spontaneous Neuronal Activity in the Early-Stage of Schizophrenia

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Ningzhi Gou

2018-05-01

Full Text Available Background: Localized abnormalities in the synchrony of spontaneous neuronal activity, measured with regional homogeneity (ReHo, has been consistently reported in patients with schizophrenia (SCZ and their unaffected siblings. To date, little is known about the genetic influences affecting the spontaneous neuronal activity in SCZ. DISC1, a strong susceptible gene for SCZ, has been implicated in neuronal excitability and synaptic function possibly associated with regional spontaneous neuronal activity. This study aimed to examine the effects of DISC1 variations on the regional spontaneous neuronal activity in SCZ.Methods: Resting-state fMRI data were obtained from 28 SCZ patients and 21 healthy controls (HC for ReHo analysis. Six single nucleotide polymorphisms (SNPs of DISC1 gene were genotyped using the PCR and direct sequencing.Results: Significant diagnosis × genotype interactions were noted for three SNPs (rs821616, rs821617, and rs2738880. For rs821617, the interactions were localized to the precuneus, basal ganglia and pre-/post-central regions. Significant interactive effects were identified at the temporal and post-central gyri for rs821616 (Ser704Cys and the inferior temporal gyrus for rs2738880. Furthermore, post-hoc analysis revealed that the DISC1 variations on these SNPs exerted different influences on ReHo between SCZ patients and HC.Conclusion: To our knowledge this is the first study to unpick the influence of DISC1 variations on spontaneous neuronal activity in SCZ; Given the emerging evidence that ReHo is a stable inheritable phenotype for schizophrenia, our findings suggest the DISC1 variations are possibly an inheritable source for the altered ReHo in this disorder.

Replication study confirms link between TSPAN18 mutation and schizophrenia in Han Chinese.

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Jianmin Yuan

Full Text Available Schizophrenia (SCZ is a severe psychiatric disorder associated with many different risk factors, both genetic and environmental. A recent genome-wide association study (GWAS of Han Chinese identified three single-nucleotide polymorphisms (SNPs rs11038167, rs11038172, and rs835784 in the tetraspanins gene TSPAN18 as possible susceptibility loci for schizophrenia. Hoping to validate these findings, we conducted a case-control study of Han Chinese with 1093 schizophrenia cases and 1022 healthy controls. Using the LDR-PCR method to genotype polymorphisms in TSPAN18, we found no significant differences (P>0.05 between patients and controls in either the allele or genotype frequency of the SNPs rs11038167 and rs11038172. We did find, however, that the frequency of the 'A' allele of SNP rs835784 is significantly higher in patients than in controls. We further observed a significant association (OR= 1.197, 95%CI= 1.047-1.369 between risk for SCZ and this 'A' allele. These results confirm the significant association, in Han Chinese populations, of increased SCZ risk and the variant of the TSPAN18 gene containing the 'A' allele of SNP rs835784.

Heritability of cortical thickness changes over time in twin pairs discordant for schizophrenia.

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Hedman, Anna M; van Haren, Neeltje E M; van Baal, G Caroline M; Brouwer, Rachel M; Brans, Rachel G H; Schnack, Hugo G; Kahn, René S; Hulshoff Pol, Hilleke E

2016-06-01

Cortical thickness and surface area changes have repeatedly been found in schizophrenia. Whether progressive loss in cortical thickness and surface area are mediated by genetic or disease related factors is unknown. Here we investigate to what extent genetic and/or environmental factors contribute to the association between change in cortical thickness and surface area and liability to develop schizophrenia. Longitudinal magnetic resonance imaging study over a 5-year interval. Monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia were compared with healthy control twin pairs using repeated measures analysis of variance (RM-ANOVA) and structural equation modeling (SEM). Twins discordant for schizophrenia and healthy control twins were recruited from the twin cohort at the University Medical Centre Utrecht, The Netherlands. A total of 90 individuals from 46 same sex twin pairs were included: 9 MZ and 10 DZ discordant for schizophrenia and 14 MZ and 13 (11 complete and 2 incomplete) DZ healthy twin-pairs. Age varied between 19 and 57years. Higher genetic liability for schizophrenia was associated with progressive global thinning of the cortex, particularly of the left superior temporal cortex. Higher environmental liability for schizophrenia was associated with global attenuated thinning of the cortex, and including of the left superior temporal cortex. Cortical surface area change was heritable, but not significantly associated with higher genetic or environmental liability for schizophrenia. Excessive cortical thinning, particularly of the left superior temporal cortex, may represent a genetic risk marker for schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.

Impact of the genome wide supported NRGN gene on anterior cingulate morphology in schizophrenia.

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Kazutaka Ohi

Full Text Available BACKGROUND: The rs12807809 single-nucleotide polymorphism in NRGN is a genetic risk variant with genome-wide significance for schizophrenia. The frequency of the T allele of rs12807809 is higher in individuals with schizophrenia than in those without the disorder. Reduced immunoreactivity of NRGN, which is expressed exclusively in the brain, has been observed in Brodmann areas (BA 9 and 32 of the prefrontal cortex in postmortem brains from patients with schizophrenia compared with those in controls. METHODS: Genotype effects of rs12807809 were investigated on gray matter (GM and white matter (WM volumes using magnetic resonance imaging (MRI with a voxel-based morphometry (VBM technique in a sample of 99 Japanese patients with schizophrenia and 263 healthy controls. RESULTS: Although significant genotype-diagnosis interaction either on GM or WM volume was not observed, there was a trend of genotype-diagnosis interaction on GM volume in the left anterior cingulate cortex (ACC. Thus, the effects of NRGN genotype on GM volume of patients with schizophrenia and healthy controls were separately investigated. In patients with schizophrenia, carriers of the risk T allele had a smaller GM volume in the left ACC (BA32 than did carriers of the non-risk C allele. Significant genotype effect on other regions of the GM or WM was not observed for either the patients or controls. CONCLUSIONS: Our findings suggest that the genome-wide associated genetic risk variant in the NRGN gene may be related to a small GM volume in the ACC in the left hemisphere in patients with schizophrenia.

Genetic diversity and antifungal susceptibility of Fusarium isolates in onychomycosis.

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Rosa, Priscila D; Heidrich, Daiane; Corrêa, Carolina; Scroferneker, Maria Lúcia; Vettorato, Gerson; Fuentefria, Alexandre M; Goldani, Luciano Z

2017-09-01

Fusarium species have emerged as an important human pathogen in skin disease, onychomycosis, keratitis and invasive disease. Onychomycosis caused by Fusarium spp. The infection has been increasingly described in the immunocompetent and immunosuppressed hosts. Considering onychomycosis is a difficult to treat infection, and little is known about the genetic variability and susceptibility pattern of Fusarium spp., further studies are necessary to understand the pathogenesis and better to define the appropriate antifungal treatment for this infection. Accordingly, the objective of this study was to describe the in vitro susceptibility to different antifungal agents and the genetic diversity of 35 Fusarium isolated from patients with onychomycosis. Fusarium spp. were isolated predominantly from female Caucasians, and the most frequent anatomical location was the nail of the hallux. Results revealed that 25 (71.4%) of isolates belonged to the Fusarium solani species complex, followed by 10 (28.5%) isolates from the Fusarium oxysporum species complex. Noteworthy, the authors report the first case of Neocosmospora rubicola isolated from a patient with onychomycosis. Amphotericin B was the most effective antifungal agent against the majority of isolates (60%, MIC ≤4 μg/mL), followed by voriconazole (34.2%, MIC ≤4 μg/mL). In general, Fusarium species presented MIC values >64 μg/mL for fluconazole, itraconazole and terbinafine. Accurate pathogen identification, characterisation and susceptibility testing provide a better understanding of pathogenesis of Fusarium in onychomycosis. © 2017 Blackwell Verlag GmbH.

Regional cerebral blood flow of the patients with schizophrenia. A study using 99mTc-ECD SPECT at rest and activation

International Nuclear Information System (INIS)

Hu Ping; Wu Kening; Zeng Shiquan; Lin Zengtao; Yu Jinlong

1996-01-01

Regional cerebral blood flow (rCBF) changes of the patients with schizophrenia were observed. 99m Tc-ECD SPECT was performed on 22 patients with schizophrenia and 10 healthy volunteers at rest and activation with a cognitive task: a modified Wisconsin Card Sorting Test. At rest state, only 4 patients have abnormal rCBF pattern: left hemisphere over-perfusion relative to the right. A significant relative activation deficit in the left inferior prefrontal region was revealed in the patients during activation. The patients with schizophrenia may have frontal lobe dysfunction

Grey matter, an endophenotype for schizophrenia? A voxel-based morphometry study in siblings of patients with schizophrenia

Science.gov (United States)

van der Velde, Jorien; Gromann, Paula M.; Swart, Marte; de Haan, Lieuwe; Wiersma, Durk; Bruggeman, Richard; Krabbendam, Lydia; Aleman, André

2015-01-01

Background Grey matter, both volume and concentration, has been proposed as an endophenotype for schizophrenia given a number of reports of grey matter abnormalities in relatives of patients with schizophrenia. However, previous studies on grey matter abnormalities in relatives have produced inconsistent results. The aim of the present study was to examine grey matter differences between controls and siblings of patients with schizophrenia and to examine whether the age, genetic loading or subclinical psychotic symptoms of selected individuals could explain the previously reported inconsistencies. Methods We compared the grey matter volume and grey matter concentration of healthy siblings of patients with schizophrenia and healthy controls matched for age, sex and education using voxel-based morphometry (VBM). Furthermore, we selected subsamples based on age (< 30 yr), genetic loading and subclinical psychotic symptoms to examine whether this would lead to different results. Results We included 89 siblings and 69 controls in our study. The results showed that siblings and controls did not differ significantly on grey matter volume or concentration. Furthermore, specifically selecting participants based on age, genetic loading or subclinical psychotic symptoms did not alter these findings. Limitations The main limitation was that subdividing the sample resulted in smaller samples for the subanalyses. Furthermore, we used MRI data from 2 different scanner sites. Conclusion These results indicate that grey matter measured through VBM might not be a suitable endophenotype for schizophrenia. PMID:25768029

Susceptibility and triggering scenarios at a regional scale for shallow landslides

Science.gov (United States)

Gullà, G.; Antronico, L.; Iaquinta, P.; Terranova, O.

2008-07-01

The work aims at identifying susceptible areas and pluviometric triggering scenarios at a regional scale in Calabria (Italy), with reference to shallow landsliding events. The proposed methodology follows a statistical approach and uses a database linked to a GIS that has been created to support the various steps of spatial data management and manipulation. The shallow landslide predisposing factors taken into account are derived from (i) the 40-m digital terrain model of the region, an ˜ 15,075 km 2 extension; (ii) outcropping lithology; (iii) soils; and (iv) land use. More precisely, a map of the slopes has been drawn from the digital terrain model. Two kinds of covers [prevalently coarse-grained (CG cover) or fine-grained (FG cover)] were identified, referring to the geotechnical characteristics of geomaterial covers and to the lithology map; soilscapes were drawn from soil maps; and finally, the land use map was employed without any prior processing. Subsequently, the inventory maps of some shallow landsliding events, totaling more than 30,000 instabilities of the past and detected by field surveys and photo aerial restitution, were employed to calibrate the relative importance of these predisposing factors. The use of single factors (first level analysis) therefore provides three different susceptibility maps. Second level analysis, however, enables better location of areas susceptible to shallow landsliding events by crossing the single susceptibility maps. On the basis of the susceptibility map obtained by the second level analysis, five different classes of susceptibility to shallow landsliding events have been outlined over the regional territory: 8.9% of the regional territory shows very high susceptibility, 14.3% high susceptibility, 15% moderate susceptibility, 3.6% low susceptibility, and finally, about 58% very low susceptibility. Finally, the maps of two significant shallow landsliding events of the past and their related rainfalls have been

Grey matter, an endophenotype for schizophrenia? A voxel-based morphometry study in siblings of patients with schizophrenia.

Science.gov (United States)

van der Velde, Jorien; Gromann, Paula M; Swart, Marte; de Haan, Lieuwe; Wiersma, Durk; Bruggeman, Richard; Krabbendam, Lydia; Aleman, André

2015-05-01

Grey matter, both volume and concentration, has been proposed as an endophenotype for schizophrenia given a number of reports of grey matter abnormalities in relatives of patients with schizophrenia. However, previous studies on grey matter abnormalities in relatives have produced inconsistent results. The aim of the present study was to examine grey matter differences between controls and siblings of patients with schizophrenia and to examine whether the age, genetic loading or subclinical psychotic symptoms of selected individuals could explain the previously reported inconsistencies. We compared the grey matter volume and grey matter concentration of healthy siblings of patients with schizophrenia and healthy controls matched for age, sex and education using voxel-based morphometry (VBM). Furthermore, we selected subsamples based on age (grey matter volume or concentration. Furthermore, specifically selecting participants based on age, genetic loading or subclinical psychotic symptoms did not alter these findings. The main limitation was that subdividing the sample resulted in smaller samples for the subanalyses. Furthermore, we used MRI data from 2 different scanner sites. These results indicate that grey matter measured through VBM might not be a suitable endophenotype for schizophrenia.

Evaluating historical candidate genes for schizophrenia

DEFF Research Database (Denmark)

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 thes...

Toxoplasma Infection in Schizophrenia Patients: A Comparative Study with Control Group

OpenAIRE

Alipour, A; Shojaee, S; Mohebali, M; Tehranidoost, M; Abdi Masoleh, F; Keshavarz, H

2011-01-01

Background: Schizophrenia is a serious, chronic, and often debilitating neuropsychiatric disor­der. Its causes are still poorly understood. Besides genetic and non-genetic (environmental) fac­tors are thought to be important as the cause of the structural and functional deficits that character­ize schizophrenia. This study aimed to compare Toxoplasma gondii infection between schizo­phrenia patients and non-schizophrenia individuals as control group.Methods: A case-control study was designed i...

Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis.

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Blokland, Gabriëlla A M; Mesholam-Gately, Raquelle I; Toulopoulou, Timothea; Del Re, Elisabetta C; Lam, Max; DeLisi, Lynn E; Donohoe, Gary; Walters, James T R; Seidman, Larry J; Petryshen, Tracey L

2017-07-01

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population. © The Author 2016. Published by Oxford University Press on behalf of

Regional Abnormality of Grey Matter in Schizophrenia: Effect from the Illness or Treatment?

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Ying Yue

Full Text Available Both schizophrenia and antipsychotic treatment are known to modulate brain morphology. However, it is difficult to establish whether observed structural brain abnormalities are due to disease or the effects of treatment. The aim of this study was to investigate the effects of illness and antipsychotic treatment on brain structures in antipsychotic-naïve first-episode schizophrenia based on a longitudinal short-term design. Twenty antipsychotic-naïve subjects with first-episode schizophrenia and twenty-four age- and sex-matched healthy controls underwent 3T MRI scans. Voxel-based morphometry (VBM was used to examine the brain structural abnormality in patients compared to healthy controls. Nine patients were included in the follow-up examination after 8 weeks of treatment. Tensor-based morphometry (TBM was used to identify longitudinal brain structural changes. We observed significantly reduced grey matter volume in the right superior temporal gyrus in antipsychotic-naïve patients with schizophrenia compared with healthy controls. After 8 weeks of treatment, patients showed significantly increased grey matter volume primarily in the bilateral prefrontal cortex, insula, right thalamus, left superior occipital cortex and the bilateral cerebellum. In addition, a greater enlargement of the prefrontal cortex is associated with the improvement in negative symptoms, and a more enlarged thalamus is associated with greater improvement in positive symptoms. Our results suggest the following: (1 the abnormality in the right superior temporal gyrus is present in the early stages of schizophrenia, possibly representing the core region related to schizophrenia; and (2 atypical antipsychotics could modulate brain morphology involving the thalamus, cortical grey matter and cerebellum. In addition, examination of the prefrontal cortex and thalamus might facilitate an efficient response to atypical antipsychotics in terms of symptom improvement.

Genetic susceptibility testing for chronic disease and intention for behavior change in healthy young adults.

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Vassy, Jason L; Donelan, Karen; Hivert, Marie-France; Green, Robert C; Grant, Richard W

2013-04-01

Genetic testing for chronic disease susceptibility may motivate young adults for preventive behavior change. This nationally representative survey gave 521 young adults hypothetical scenarios of receiving genetic susceptibility results for heart disease, type 2 diabetes, and stroke and asked their (1) interest in such testing, (2) anticipated likelihood of improving diet and physical activity with high- and low-risk test results, and (3) readiness to make behavior change. Responses were analyzed by presence of established disease-risk factors. Respondents with high phenotypic diabetes risk reported increased likelihood of improving their diet and physical activity in response to high-risk results compared with those with low diabetes risk (odds ratio (OR), 1.82 (1.03, 3.21) for diet and OR, 2.64 (1.24, 5.64) for physical activity). In contrast, poor baseline diet (OR, 0.51 (0.27, 0.99)) and poor physical activity (OR, 0.53 (0.29, 0.99)) were associated with decreased likelihood of improving diet. Knowledge of genetic susceptibility may motivate young adults with higher personal diabetes risk for improvement in diet and exercise, but poor baseline behaviors are associated with decreased intention to make these changes. To be effective, genetic risk testing in young adults may need to be coupled with other strategies to enable behavior change.

Are Adolescents with ADHD Interested in Genetic Testing for Nicotine Addiction Susceptibility?

Directory of Open Access Journals (Sweden)

Linda J. Herbert

2010-04-01

Full Text Available It has been well-established that some adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD are at increased risk for cigarette smoking. Current research on the genetic basis of this association could ultimately translate into genetic tests capable of identifying smoking-prone adolescents with ADHD. In this study we examined 81 ADHD affected adolescents’ (age 13–21 interest in genetic testing for nicotine addiction susceptibility. Fifty-seven percent of adolescents indicated a fair amount of interest or more in testing. Most adolescents indicated that the personal information revealed from testing would be either useful (29% or interesting (37%. Implications for genetically-informed smoking prevention and cessation interventions in high risk adolescents with ADHD are discussed.

Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

DEFF Research Database (Denmark)

de Jong, Simone; van Eijk, Kristel R; Zeegers, Dave W L H

2012-01-01

of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs...

Associations of common copy number variants in glutathione S-transferase mu 1 and D-dopachrome tautomerase-like protein genes with risk of schizophrenia in a Japanese population.

Science.gov (United States)

Nakamura, Toru; Ohnuma, Tohru; Hanzawa, Ryo; Takebayashi, Yuto; Takeda, Mayu; Nishimon, Shohei; Sannohe, Takahiro; Katsuta, Narimasa; Higashiyama, Ryoko; Shibata, Nobuto; Arai, Heii

2015-10-01

Oxidative-stress, genetic regions of interest (1p13 and 22q11), and common copy number variations (CNVs) may play roles in the pathophysiology of schizophrenia. In the present study, we confirmed associations between schizophrenia and the common CNVs in the glutathione (GSH)-related genes GSTT1, DDTL, and GSTM1 using quantitative real-time polymerase chain reaction analyses of 620 patients with schizophrenia and in 622 controls. No significant differences in GSTT1 copy number distributions were found between patient groups. However, frequencies of characterized CNVs and assumed gain alleles of DDTL and GSTM1 were significantly higher in patients with schizophrenia. In agreement with a previous report, the present data indicate that gains in the CNV alleles DDTL and GSTM1 are genetic risk factors in Japanese patients with schizophrenia, and suggest involvement of micro-inflammation and oxidative stress in the pathophysiology of schizophrenia. © 2015 Wiley Periodicals, Inc.

Association Between rs1344706 of ZNF804A and Schizophrenia: A Meta-analysis

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Meiyan Zhu

2014-12-01

Full Text Available Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism (SNP rs1344706 in the gene ZNF804A encoding zinc finger protein 804A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of PubMed database identified 25 case–control studies with available genotype frequencies of rs1344706 for the meta-analysis, involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio (OR with 95% confidence interval (CI was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations (P = 0.028, OR = 1.138, 95% CI: 1.014–1.278; P = 0.004 for heterogeneity and Asian populations (P = 0.008, OR = 1.092, 95% CI: 1.023–1.165; P = 0.001 for heterogeneity, but not in other populations (P = 0.286, OR = 1.209, 95% CI: 0.853–1.714, P = 0.120 for heterogeneity. Egger’s test (P > 0.05 and Begg’s test (P > 0.05 are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.

Genetic variant of miR-4293 rs12220909 is associated with susceptibility to non-small cell lung cancer in a Chinese Han population.

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Lixia Fan

Full Text Available Non-small cell lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Genetic variants in regulatory regions of some miRNAs might be involved in non-small cell lung cancer susceptibility and survival. rs12220909 (G/C genetic polymorphism in miR-4293 has been shown to be associated with decreased risk of esophageal squamous cell carcinoma. However, the influence of rs12220909 genetic variation on non-small cell lung cancer susceptibility has not been reported. In order to evaluate the potential association between miR-4293 rs12220909 and non-small cell lung cancer risk in a Chinese population, we performed a case-control study among 998 non-small cell lung cancer cases and 1471 controls. The data shows that miR-4293 rs12220909 was significantly associated with decreased susceptibility to non-small cell lung cancer (GC vs.GG: OR = 0.681, 95%CI = 0.555-0.835, P = 2.19E-4; GG vs. GC+CC: OR = 0.687, 95%CI = 0.564-0.837, P = 1.95E-4, which indicates that rs12220909 in miR-4293 may play a significant role in the development of non-small cell lung cancer.

The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study.

Science.gov (United States)

Cederlöf, Martin; Bergen, Sarah E; Långström, Niklas; Larsson, Henrik; Boman, Marcus; Craddock, Nick; Östberg, Per; Lundström, Sebastian; Sjölander, Arvid; Nordlind, Klas; Landén, Mikael; Lichtenstein, Paul

2015-05-01

Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question. We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions. Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8). The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

Science.gov (United States)

Bassett, Anne S; Lowther, Chelsea; Merico, Daniele; Costain, Gregory; Chow, Eva W C; van Amelsvoort, Therese; McDonald-McGinn, Donna; Gur, Raquel E; Swillen, Ann; Van den Bree, Marianne; Murphy, Kieran; Gothelf, Doron; Bearden, Carrie E; Eliez, Stephan; Kates, Wendy; Philip, Nicole; Sashi, Vandana; Campbell, Linda; Vorstman, Jacob; Cubells, Joseph; Repetto, Gabriela M; Simon, Tony; Boot, Erik; Heung, Tracy; Evers, Rens; Vingerhoets, Claudia; van Duin, Esther; Zackai, Elaine; Vergaelen, Elfi; Devriendt, Koen; Vermeesch, Joris R; Owen, Michael; Murphy, Clodagh; Michaelovosky, Elena; Kushan, Leila; Schneider, Maude; Fremont, Wanda; Busa, Tiffany; Hooper, Stephen; McCabe, Kathryn; Duijff, Sasja; Isaev, Karin; Pellecchia, Giovanna; Wei, John; Gazzellone, Matthew J; Scherer, Stephen W; Emanuel, Beverly S; Guo, Tingwei; Morrow, Bernice E; Marshall, Christian R

2017-11-01

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression. Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia. Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

Genetic variations of MMP9 gene and intracerebral hemorrhage susceptibility: a case-control study in Chinese Han population.

Science.gov (United States)

Yang, Jie; Wu, Bo; Lin, Sen; Zhou, Junshan; Li, Yingbin; Dong, Wei; Arima, Hisatomi; Zhang, Chanfei; Liu, Yukai; Liu, Ming

2014-06-15

To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population. The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility. 181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 ± 13.27 vs. 72.44 ± 12.71 years, ppopulation. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p>0.05). The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population. Copyright © 2014 Elsevier B.V. All rights reserved.

Future management of human obesity: understanding the meaning of genetic susceptibility

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Jenkins AB

2014-12-01

Full Text Available Arthur B Jenkins,1,2 Lesley V Campbell2,3 1School of Medicine, University of Wollongong, Wollongong, NSW, Australia; 2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; 3Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, NSW, Australia Abstract: Gene–environment interactions are central to the expression of obesity. The condition is strongly heritable (ie, genetic, and most of the variation in obesity levels between countries and between individuals can be explained by the effects of obesogenic environments on individual genetic susceptibilities. The nature of the obesogenic environmental influences is not clear in detail, but they correlate closely with measures of affluence. The causes of variation in genetic susceptibility are also not clearly defined, but their general nature has become clearer. The failure of genome-wide association studies or large linkage studies to identify or replicate causative genetic variants, together with the segregation of obesity-related traits in families, implicates a heterogenetic mechanism in which rare, dominantly or additively expressed genetic variants are responsible for most of common obesity. The search for rare causative variants continues with some successes, but those identified contribute very little to the overall burden and, assuming heterogenetics, there are many more to find. The time when genomic risk factors provide more information than do currently available markers, such as family history, is a long way off. Genomic studies to date have contributed little, if anything, to the prevention and treatment of common obesity and its associated disorders. This contrasts with the obvious and immediate potential implications of the well-established overall genetic basis of obesity, which have not yet been exploited in the clinical or public health arenas. Genomic studies, which have helped to define the genetic basis of

[Epigenetics of schizophrenia: a review].

Science.gov (United States)

Rivollier, F; Lotersztajn, L; Chaumette, B; Krebs, M-O; Kebir, O

2014-10-01

Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post

Brain-Derived Neurotrophic Factor Expression in Individuals With Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia.

Science.gov (United States)

Islam, Farhana; Mulsant, Benoit H; Voineskos, Aristotle N; Rajji, Tarek K

2017-07-01

Schizophrenia has been hypothesized to be a syndrome of accelerated aging. Brain plasticity is vulnerable to the normal aging process and affected in schizophrenia: brain-derived neurotrophic factor (BDNF) is an important neuroplasticity molecule. The present review explores the accelerated aging hypothesis of schizophrenia by comparing changes in BDNF expression in schizophrenia with aging-associated changes. Individuals with schizophrenia show patterns of increased overall mortality, metabolic abnormalities, and cognitive decline normally observed later in life in the healthy population. An overall decrease is observed in BDNF expression in schizophrenia compared to healthy controls and in older individuals compared to a younger cohort. There is a marked decrease in BDNF levels in the frontal regions and in the periphery among older individuals and those with schizophrenia; however, data for BDNF expression in the occipital, parietal, and temporal cortices and the hippocampus is inconclusive. Accelerated aging hypothesis is supported based on frontal regions and peripheral studies; however, further studies are needed in other brain regions.

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

DEFF Research Database (Denmark)

Severinsen, Jacob; Bjarkam, Carsten; Kiær-Larsen, Stine

Introduction: Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample we previously reported association between microsatellite markers located at 22q13.31-qtel and both...... disorders. Methods: The present study reports an association analysis across 5 genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. Results: The bromodomain-containing 1 gene (BRD1), which...... encodes a putative regulator of transcription showed association with both disorders with minimal p-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker “risk” haplotype showed a frequency of ~10% in the combined case group versus ~1...

[Association of Schizophrenia and its Clinical Implications with the NOS1AP Gene in the Colombian Population].

Science.gov (United States)

Valencia, Jenny García; Duarte, Ana Victoria Valencia; Vila, Ana Lucía Páez; Kremeyer, Bárbara; Montoya, María Patricia Arbeláez; Linares, Andrés Ruiz; Acosta, Carlos Alberto Palacio; Duque, Jorge Ospina; Berrío, Gabriel Bedoya

2012-06-01

The nitric oxide synthase 1 adaptor protein (NOS1AP) gene is possibly implicated in schizophrenia etiopathogenesis. To determine the association of NOS1AP gene variants with schizophrenia and the relationship of variants with the clinical dimensions of the disorder in the Colombian population. It is a case-control study with 255 subjects per group. Markers within the NOS1AP gene were typified as well as other informative material of genetic origin so as to adjust by population stratification. A factorial analysis of the main components for each item in the Scales for Evaluating Negative Symptoms (SENS) together with the Scales for Evaluating Positive Symptoms (SEPS) to determine clinical dimensions. Association between the C/C genotype of the rs945713 marker with schizophrenia (OR = 1.79, 95% CI: 1.13 - 2.84) was found. The C/C genotype of the rs945713 was related to higher scores in the "affective flattening and alogia" dimension; and the A/A genotype of the rs4657181 marker was associated to lower scores in the same dimension. Significant associations of markers inside the NOS1AP gene with schizophrenia and the "affective flattening and alogia" clinical dimension were found. These results are consistent with previous studies and support the possibility that NOS1AP influences schizophrenia susceptibility. Furthermore, NOS1AP might be a modifier of schizophrenia clinical characteristics. Copyright © 2012 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

Directory of Open Access Journals (Sweden)

Stella Koutros

Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

[Influence of paternal age in schizophrenia].

Science.gov (United States)

Hubert, A; Szöke, A; Leboyer, M; Schürhoff, F

2011-06-01

Schizophrenia is an aetiologically heterogeneous syndrome, with a strong genetic component. Despite a reduced fertility in this disorder, its prevalence is maintained and could be explained by de novo genetic mutations. Advanced paternal age (APA) is a major source of new mutations in human beings and could thus be associated with an increased risk of developing schizophrenia in offspring. New mutations related to APA have been implicated as a cause of sporadic cases in several autosomal dominant diseases and also in neurodevelopmental diseases, autism, intellectual disabilities, and social functioning. The aim of the present study was to summarize the results of studies investigating the role of APA, and to discuss some interpretations. All relevant studies were identified through the National Library of Medicine (PubMed(®) database). Keywords used for research were "age" and "schizophrenia" linked to "paternal or father". We have identified and analysed eight cohort studies, five case-control studies, two meta-analyses, and one review concerning different father's mutations potentially transmitted, two studies comparing paternal age at conception between sporadic versus familial cases of schizophrenia. All studies selected have been published between 2000 and 2009. After controlling for several confounding factors including maternal age, the relative risk of schizophrenia increased from 1.84 to 4.62 in offspring of fathers with an older age of fatherhood. Mother's age showed no significant effects after adjusting for paternal age. There was a significant association between paternal age and risk of developing schizophrenia, there was a weaker association with psychosis. The results of these different studies are confirmed by two recent meta-analyses which found an increased risk of schizophrenia in offspring of fathers older than 35 years. Two main hypotheses could explain these results. The first one is based on the presence of new mutations in the

Theory of mind reasoning in schizophrenia patients and non-psychotic relatives.

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Cassetta, Briana; Goghari, Vina

2014-08-15

Research consistently demonstrates that schizophrenia patients have theory of mind (ToM) impairments. Additionally, there is some evidence that family members of schizophrenia patients also demonstrate impairments in ToM, suggesting a genetic vulnerability for the disorder. This study assessed ToM abilities (i.e., sarcasm comprehension) in schizophrenia patients and their first-degree biological relatives during video-taped social interactions, to be representative of real-world interactions and to assess for disease-specific and/or genetic liability effects. Additionally, we assessed whether ToM abilities predicted social and global functioning in schizophrenia patients, and whether symptoms were associated with ToM deficits. Schizophrenia patients demonstrated impairments in sarcasm comprehension compared to controls and relatives, whereas relatives showed intact comprehension. Symptoms of schizophrenia significantly predicted worse ToM abilities. Furthermore, in schizophrenia patients, impaired ToM reasoning predicted worse social and global functioning. Given schizophrenia patients demonstrated impairments in ToM reasoning in a task that resembles real-life interactions, this might be a key area for remediation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

First Episode Schizophrenia Regional Cerebral Blood Flow Assessment after Atypical Antipsychotics

International Nuclear Information System (INIS)

Rimbu, A.; Mititelu, R.; Marinescu, G.; Ghita, S.; Mazilu, C.; Codorean, I.; Gheorghe, M.

2006-01-01

Full text: Aim: Since regional cerebral blood flow (rCBF) findings in schizophrenic patients are inconsistent, the aim of our study was to evaluate and compare rCBF in the first episode of schizophrenia, before and after atypical antipsychotic treatment. Method: 21 patients who met criteria for schizophrenia were assessed PANSS score and tomographic brain perfusion (SPECT). The treatment was administered for 10-12 weeks and the dose was 4.8mg/day Risperidone, 11.6mg/day Olanzepine, 440mg/day Quetiapine. After finishing treatment all patients underwent a control SPECT study. Results: PANSS scores revealed two groups: group A-14 patients with predominant positive symptoms; 9 received Olanzapine and 5 Quetiapine. In group B -7 patients with predominant negative symptoms received Risperidone. Positive symptoms were associated with hypoperfusion in posterior parietal regions and superior temporal gyrus, bilaterally; for negative symptoms we found hypoperfusion in prefrontal cortex, predominantly in left side and a hyper perfusion in left basal ganglia. All patients that received atypical antipsychotic drugs had clinical improvement and decreases in PANSS scores; the control SPECT analysis revealed the same cortical changes as first studies in 15 patients and an increase of the rCBF in frontal lobes for 4 patients. 14 patients we noticed an increased rCBF at subcortical level, especially in left caudate nuclei. Conclusions: We found nonspecific features of rCBF in patients with first episode of schizophrenia, suggesting a perfusion dynamic balance rather than a fixed model. Those aspects are much more related to clinical symptoms, than to the therapeutical response. The rCBF changes in subcortical level after treatment (64.4% increase of rCBF; 35.6% not modified), can have a good prognostic value for therapeutic response. (author)

The role of genes, stress and dopamine in the development of schizophrenia

Science.gov (United States)

Howes, Oliver D; McCutcheon, Robert; Owen, Michael J; Murray, Robin

2017-01-01

The dopamine hypothesis is the longest standing pathoaetiological theory of schizophrenia. As it was initially based on indirect evidence and findings in patients with established schizophrenia it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity, and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in-line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also impact on presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis and psychosocial stress. Included among the many genes associated with risk of schizophrenia, are the gene encoding the DRD2 receptor and those involved in the up-stream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acid (GABA)-ergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitise the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients. PMID:27720198

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry

DEFF Research Database (Denmark)

Hulshoff Pol, HE; Schnack, HG; Mandl, RC

2006-01-01

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions...... best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control...... twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex...

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.

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Uezato, Akihito; Yamamoto, Naoki; Jitoku, Daisuke; Haramo, Emiko; Hiraaki, Eri; Iwayama, Yoshimi; Toyota, Tomoko; Umino, Masakazu; Umino, Asami; Iwata, Yasuhide; Suzuki, Katsuaki; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Kurumaji, Akeo; Yoshikawa, Takeo; Nishikawa, Toru

2017-12-01

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development. © 2017 Wiley Periodicals, Inc.

HLA DRB1*03 as a possible common etiology of schizophrenia, Graves' disease, and type 2 diabetes.

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Sayeh, Aicha; Ben Cheikh, Cheker; Mardessi, Ali; Mrad, Meriem; Nsiri, Brahim; Oumaya, Abdelaziz; Fekih-Mrissa, Najiba

2017-01-01

Autoimmune diseases and schizophrenia share many common features. Association studies confirm a shared genetic association in the human leukocyte antigen (HLA) region between schizophrenia and most autoimmune diseases. To our knowledge, the simultaneous syndromes of Graves' disease (GD) and type 2 diabetes (T2D) in schizophrenia are rare in Tunisia. We report a case of a 42-year-old woman admitted to the department of psychiatry for an acute relapse of chronic schizophrenia. Her medical history revealed that she was followed for Graves' disease and for a type 2 diabetes mellitus. A low-resolution HLA typing was performed by polymerase chain reaction sequence-specific primer (PCR-SSP) techniques according to determine the patient's haplotype. Our study suggests that the HLA DRB1*03 allele may explain a common etiology underlying the co-morbidity of Graves' disease, type 2 diabetes, and schizophrenia in our patient.

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Science.gov (United States)

McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

2017-01-01

Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

A family affair: brain abnormalities in siblings of patients with schizophrenia

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Hulshoff Pol, Hilleke; Gogtay, Nitin

2013-01-01

Schizophrenia is a severe mental disorder that has a strong genetic basis. Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with earlier onset cases resulting in more profound brain abnormalities. Siblings of patients with schizophrenia provide an invaluable resource for differentiating between trait and state markers, thus highlighting possible endophenotypes for ongoing research. However, findings from sibling studies have not been systematically put together in a coherent story across the broader age span. We review here the cortical grey matter abnormalities in siblings of patients with schizophrenia from childhood to adulthood, by reviewing sibling studies from both childhood-onset schizophrenia, and the more common adult-onset schizophrenia. When reviewed together, studies suggest that siblings of patients with schizophrenia display significant brain abnormalities that highlight both similarities and differences between the adult and childhood populations, with shared developmental risk patterns, and segregating trajectories. Based on current research it appears that the cortical grey matter abnormalities in siblings are likely to be an age-dependent endophenotype, which normalize by the typical age of onset of schizophrenia unless there has been more genetic or symptom burdening. With increased genetic burdening (e.g. discordant twins of patients) the grey matter abnormalities in (twin) siblings are progressive in adulthood. This synthesis of the literature clarifies the importance of brain plasticity in the pathophysiology of the illness, indicating that probands may lack protective factors critical for healthy development. PMID:23698280

Application of a hybrid model of neural networks and genetic algorithms to evaluate landslide susceptibility

Science.gov (United States)

Wang, H. B.; Li, J. W.; Zhou, B.; Yuan, Z. Q.; Chen, Y. P.

2013-03-01

In the last few decades, the development of Geographical Information Systems (GIS) technology has provided a method for the evaluation of landslide susceptibility and hazard. Slope units were found to be appropriate for the fundamental morphological elements in landslide susceptibility evaluation. Following the DEM construction in a loess area susceptible to landslides, the direct-reverse DEM technology was employed to generate 216 slope units in the studied area. After a detailed investigation, the landslide inventory was mapped in which 39 landslides, including paleo-landslides, old landslides and recent landslides, were present. Of the 216 slope units, 123 involved landslides. To analyze the mechanism of these landslides, six environmental factors were selected to evaluate landslide occurrence: slope angle, aspect, the height and shape of the slope, distance to river and human activities. These factors were extracted in terms of the slope unit within the ArcGIS software. The spatial analysis demonstrates that most of the landslides are located on convex slopes at an elevation of 100-150 m with slope angles from 135°-225° and 40°-60°. Landslide occurrence was then checked according to these environmental factors using an artificial neural network with back propagation, optimized by genetic algorithms. A dataset of 120 slope units was chosen for training the neural network model, i.e., 80 units with landslide presence and 40 units without landslide presence. The parameters of genetic algorithms and neural networks were then set: population size of 100, crossover probability of 0.65, mutation probability of 0.01, momentum factor of 0.60, learning rate of 0.7, max learning number of 10 000, and target error of 0.000001. After training on the datasets, the susceptibility of landslides was mapped for the land-use plan and hazard mitigation. Comparing the susceptibility map with landslide inventory, it was noted that the prediction accuracy of landslide occurrence

Comorbid obsessive-compulsive symptoms in schizophrenia: contributions of pharmacological and genetic factors

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Frederike eSchirmbeck

2013-08-01

Full Text Available A large subgroup of around 25% of schizophrenia patients suffers from obsessive-compulsive symptoms (OCS and about 12% fulfil the diagnostic criteria of obsessive-compulsive disorder (OCD. The additional occurrence of OCS is associated with high subjective burden of disease, additional neurocognitive impairment, poorer social and vocational functioning, greater service utilization and high levels of anxiety and depression. Comorbid patients can be assigned to heterogeneous subgroups. One hypothesis assumes that second generation antipsychotics (SGAs, most importantly clozapine, might aggravate or even induce second-onset OCS. Several arguments support this assumption, most importantly the observed chronological order of first psychotic manifestation, start of treatment with clozapine and onset of OCS. In addition, correlations between OCS-severity and dose and serum levels and duration of clozapine treatment hint towards a dose-dependent side effect. It has been hypothesized that genetic risk-factors dispose patients with schizophrenia to develop OCS. One study in a South Korean sample reported associations with polymorphisms in the gene SLC1A1 (solute carrier family 1A1 and SGA-induced OCS. However, this finding could not be replicated in European patients. Preliminary results also suggest an involvement of polymorphisms in the BDNF gene (brain-derived neurotrophic factor and an interaction between markers of SLC1A1 and the gene DLGAP3 (disc large associated protein 3 as well as GRIN2B (N-methyl-D-aspartate receptor subunit 2B. Further research of well-defined samples, in particular studies investigating possible interactions of genetic risk-constellations and pharmacodynamic properties, are needed to clarify the assumed development of SGA-induced OCS. Results might improve pathogenic concepts and facilitate the definition of at risk populations, early detection and monitoring of OCS as well as multimodal therapeutic interventions.

Expression weighted cell type enrichments reveal genetic and cellular nature of major brain disorders

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Nathan Gerald Skene

2016-01-01

Full Text Available The cell types that trigger the primary pathology in many brain diseases remain largely unknown. One route to understanding the primary pathological cell type for a particular disease is to identify the cells expressing susceptibility genes. Although this is straightforward for monogenic conditions where the causative mutation may alter expression of a cell type specific marker, methods are required for the common polygenic disorders. We developed the Expression Weighted Cell Type Enrichment (EWCE method that uses single cell transcriptomes to generate the probability distribution associated with a gene list having an average level of expression within a cell type. Following validation, we applied EWCE to human genetic data from cases of epilepsy, Schizophrenia, Autism, Intellectual Disability, Alzheimer’s disease, Multiple Sclerosis and anxiety disorders. Genetic susceptibility primarily affected microglia in Alzheimer’s and Multiple Sclerosis; was shared between interneurons and pyramidal neurons in Autism and Schizophrenia; while intellectual disabilities and epilepsy were attributable to a range of cell-types, with the strongest enrichment in interneurons. We hypothesised that the primary cell type pathology could trigger secondary changes in other cell types and these could be detected by applying EWCE to transcriptome data from diseased tissue. In Autism, Schizophrenia and Alzheimer’s disease we find evidence of pathological changes in all of the major brain cell types. These findings give novel insight into the cellular origins and progression in common brain disorders. The methods can be applied to any tissue and disorder and have applications in validating mouse models.

Probing GABA Receptor Function in Schizophrenia with Iomazenil

OpenAIRE

Ahn, Kyungheup; Gil, Roberto; Seibyl, John; Sewell, Richard Andrew; D'Souza, Deepak Cyril

2010-01-01

Several lines of evidence from post-mortem, brain imaging, and genetic studies in schizophrenia patients suggest that Gamma-amino butyric acid (GABA) deficits may contribute to the pathophysiology of schizophrenia. Pharmacological induction of a transient GABA-deficit state has been shown to enhance vulnerability of healthy subjects to the psychotomimetic effects of various drugs. Exacerbating or creating a GABA deficit was hypothesized to induce or unmask psychosis in schizophrenia patients,...

Strong family history and early onset of schizophrenia: about 2 ...

African Journals Online (AJOL)

Schizophrenia is a highly heritable psychotic disorder and high genetic loading is associated with early onset of the disease. The outcome of schizophrenia has also been linked with the age of onset as well as the presence of family history of the disease. Therefore families with patients with early onset Schizophrenia are ...

Identification of shared genetic susceptibility locus for coronary artery disease, type 2 diabetes and obesity: a meta-analysis of genome-wide studies

Directory of Open Access Journals (Sweden)

Wu Chaoneng

2012-06-01

Full Text Available Abstract Type 2 diabetes (2DM, obesity, and coronary artery disease (CAD are frequently coexisted being as key components of metabolic syndrome. Whether there is shared genetic background underlying these diseases remained unclear. We performed a meta-analysis of 35 genome screens for 2DM, 36 for obesity or body mass index (BMI-defined obesity, and 21 for CAD using genome search meta-analysis (GSMA, which combines linkage results to identify regions with only weak evidence and provide genetic interactions among different diseases. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to the best linkage evidence within each bin. For each disease, bin 6.2 achieved genomic significanct evidence, and bin 9.3, 10.5, 16.3 reached suggestive level for 2DM. Bin 11.2 and 16.3, and bin 10.5 and 9.3, reached suggestive evidence for obesity and CAD respectively. In pooled all three diseases, bin 9.3 and 6.5 reached genomic significant and suggestive evidence respectively, being relatively much weaker for 2DM/CAD or 2DM/obesity or CAD/obesity. Further, genomewide significant evidence was observed of bin 16.3 and 4.5 for 2DM/obesity, which is decreased when CAD was added. These findings indicated that bin 9.3 and 6.5 are most likely to be shared by 2DM, obesity and CAD. And bin 16.3 and 4.5 are potentially common regions to 2DM and obesity only. The observed shared susceptibility regions imply a partly overlapping genetic aspects of disease development. Fine scanning of these regions will definitely identify more susceptibility genes and causal variants.

A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype.

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Johanna Hass

Full Text Available Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328. A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170 on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10 had p-values between 6.75×10(-6 and 8.3×10(-7. Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings

A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport

Energy Technology Data Exchange (ETDEWEB)

Balmain, Allan [University of California, San Francisco; Song, Ihn Young [University of California, San Francisco

2013-05-15

The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularly when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a Systems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.

Genetic susceptibility to infectious disease: lessons from mouse models of leishmaniasis

Czech Academy of Sciences Publication Activity Database

Lipoldová, Marie; Demant, P.

2006-01-01

Roč. 7, č. 4 (2006), s. 294-305 ISSN 1471-0056 R&D Projects: GA ČR(CZ) GA310/03/1381 Grant - others:Howard Hughes Medical Institute(US) HHMI55000323 Institutional research plan: CEZ:AV0Z50520514 Keywords : leishmaniasis * susceptibility to infectious disease * modifying genes Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 22.947, year: 2006

Altered Cerebral Blood Flow Covariance Network in Schizophrenia.

Science.gov (United States)

Liu, Feng; Zhuo, Chuanjun; Yu, Chunshui

2016-01-01

Many studies have shown abnormal cerebral blood flow (CBF) in schizophrenia; however, it remains unclear how topological properties of CBF network are altered in this disorder. Here, arterial spin labeling (ASL) MRI was employed to measure resting-state CBF in 96 schizophrenia patients and 91 healthy controls. CBF covariance network of each group was constructed by calculating across-subject CBF covariance between 90 brain regions. Graph theory was used to compare intergroup differences in global and nodal topological measures of the network. Both schizophrenia patients and healthy controls had small-world topology in CBF covariance networks, implying an optimal balance between functional segregation and integration. Compared with healthy controls, schizophrenia patients showed reduced small-worldness, normalized clustering coefficient and local efficiency of the network, suggesting a shift toward randomized network topology in schizophrenia. Furthermore, schizophrenia patients exhibited altered nodal centrality in the perceptual-, affective-, language-, and spatial-related regions, indicating functional disturbance of these systems in schizophrenia. This study demonstrated for the first time that schizophrenia patients have disrupted topological properties in CBF covariance network, which provides a new perspective (efficiency of blood flow distribution between brain regions) for understanding neural mechanisms of schizophrenia.

Schizophrenia risk from complex variation of complement component 4

NARCIS (Netherlands)

Sekar, Aswin; Bialas, Allison R.; de Rivera, Heather; Davis, Avery; Hammond, Timothy R.; Kamitaki, Nolan; Tooley, Katherine; Presumey, Jessy; Baum, Matthew; van Doren, Vanessa; Genovese, Giulio; Rose, Samuel A.; Handsaker, Robert E.; Daly, Mark J.; Carroll, Michael C.; Stevens, Beth; McCarroll, Steven A.; Ripke, Stephan; Neale, Benjamin M.; Corvin, Aiden; Walters, James T. R.; Farh, Kai-How; Holmans, Peter A.; Lee, Phil; Bulik-Sullivan, Brendan; Collier, David A.; Huang, Hailiang; Pers, Tune H.; Agartz, Ingrid; Agerbo, Esben; Albus, Margot; Alexander, Madeline; Amin, Farooq; Bacanu, Silviu A.; Begemann, Martin; Belliveau, Richard A.; Bene, Judit; Bergen, Sarah E.; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; de Haan, Lieuwe

2016-01-01

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging

Temporal lobe structures and facial emotion recognition in schizophrenia patients and nonpsychotic relatives.

Science.gov (United States)

Goghari, Vina M; Macdonald, Angus W; Sponheim, Scott R

2011-11-01

Temporal lobe abnormalities and emotion recognition deficits are prominent features of schizophrenia and appear related to the diathesis of the disorder. This study investigated whether temporal lobe structural abnormalities were associated with facial emotion recognition deficits in schizophrenia and related to genetic liability for the disorder. Twenty-seven schizophrenia patients, 23 biological family members, and 36 controls participated. Several temporal lobe regions (fusiform, superior temporal, middle temporal, amygdala, and hippocampus) previously associated with face recognition in normative samples and found to be abnormal in schizophrenia were evaluated using volumetric analyses. Participants completed a facial emotion recognition task and an age recognition control task under time-limited and self-paced conditions. Temporal lobe volumes were tested for associations with task performance. Group status explained 23% of the variance in temporal lobe volume. Left fusiform gray matter volume was decreased by 11% in patients and 7% in relatives compared with controls. Schizophrenia patients additionally exhibited smaller hippocampal and middle temporal volumes. Patients were unable to improve facial emotion recognition performance with unlimited time to make a judgment but were able to improve age recognition performance. Patients additionally showed a relationship between reduced temporal lobe gray matter and poor facial emotion recognition. For the middle temporal lobe region, the relationship between greater volume and better task performance was specific to facial emotion recognition and not age recognition. Because schizophrenia patients exhibited a specific deficit in emotion recognition not attributable to a generalized impairment in face perception, impaired emotion recognition may serve as a target for interventions.

Disrupted Olfactory Integration in Schizophrenia: Functional Connectivity Study.

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Kiparizoska, Sara; Ikuta, Toshikazu

2017-09-01

Evidence for olfactory dysfunction in schizophrenia has been firmly established. However, in the typical understanding of schizophrenia, olfaction is not recognized to contribute to or interact with the illness. Despite the solid presence of olfactory dysfunction in schizophrenia, its relation to the rest of the illness remains largely unclear. Here, we aimed to examine functional connectivity of the olfactory bulb, olfactory tract, and piriform cortices and isolate the network that would account for the altered olfaction in schizophrenia. We examined the functional connectivity of these specific olfactory regions in order to isolate other brain regions associated with olfactory processing in schizophrenia. Using the resting state functional MRI data from the Center for Biomedical Research Excellence in Brain Function and Mental Illness, we compared 84 patients of schizophrenia and 90 individuals without schizophrenia. The schizophrenia group showed disconnectivity between the anterior piriform cortex and the nucleus accumbens, between the posterior piriform cortex and the middle frontal gyrus, and between the olfactory tract and the visual cortices. The current results suggest functional disconnectivity of olfactory regions in schizophrenia, which may account for olfactory dysfunction and disrupted integration with other sensory modalities in schizophrenia. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Altered intrinsic and extrinsic connectivity in schizophrenia.

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Zhou, Yuan; Zeidman, Peter; Wu, Shihao; Razi, Adeel; Chen, Cheng; Yang, Liuqing; Zou, Jilin; Wang, Gaohua; Wang, Huiling; Friston, Karl J

2018-01-01

Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self-connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia.

The biochemical womb of schizophrenia: A review.

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Gaur, N; Gautam, S; Gaur, M; Sharma, P; Dadheech, G; Mishra, S

2008-10-01

The conclusive identification of specific etiological factors or pathogenic processes in the illness of schizophrenia has remained elusive despite great technological progress. The convergence of state-of-art scientific studies in molecular genetics, molecular neuropathophysiology, in vivo brain imaging and psychopharmacology, however, indicates that we may be coming much closer to understanding the genesis of schizophrenia. In near future, the diagnosis and assessment of schizophrenia using biochemical markers may become a "dream come true" for the medical community as well as for the general population. An understanding of the biochemistry/ visa vis pathophysiology of schizophrenia is essential to the discovery of preventive measures and therapeutic intervention.

Schizophrenia: A Pathogenetic Autoimmune Disease Caused by Viruses and Pathogens and Dependent on Genes

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C. J. Carter

2011-01-01

Full Text Available Many genes have been implicated in schizophrenia as have viral prenatal or adult infections and toxoplasmosis or Lyme disease. Several autoantigens also target key pathology-related proteins. These factors are interrelated. Susceptibility genes encode for proteins homologous to those of the pathogens while the autoantigens are homologous to pathogens' proteins, suggesting that the risk-promoting effects of genes and risk factors are conditional upon each other, and dependent upon protein matching between pathogen and susceptibility gene products. Pathogens' proteins may act as dummy ligands, decoy receptors, or via interactome interference. Many such proteins are immunogenic suggesting that antibody mediated knockdown of multiple schizophrenia gene products could contribute to the disease, explaining the immune activation in the brain and lymphocytes in schizophrenia, and the preponderance of immune-related gene variants in the schizophrenia genome. Schizophrenia may thus be a “pathogenetic” autoimmune disorder, caused by pathogens, genes, and the immune system acting together, and perhaps preventable by pathogen elimination, or curable by the removal of culpable antibodies and antigens.

Patterns of Dysmorphic Features in Schizophrenia

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Scutt, L.E.; Chow, E.W.C.; Weksberg, R.; Honer, W.G.; Bassett, Anne S.

2011-01-01

Congenital dysmorphic features are prevalent in schizophrenia and may reflect underlying neurodevelopmental abnormalities. A cluster analysis approach delineating patterns of dysmorphic features has been used in genetics to classify individuals into more etiologically homogeneous subgroups. In the present study, this approach was applied to schizophrenia, using a sample with a suspected genetic syndrome as a testable model. Subjects (n = 159) with schizophrenia or schizoaffective disorder were ascertained from chronic patient populations (random, n=123) or referred with possible 22q11 deletion syndrome (referred, n = 36). All subjects were evaluated for presence or absence of 70 reliably assessed dysmorphic features, which were used in a three-step cluster analysis. The analysis produced four major clusters with different patterns of dysmorphic features. Significant between-cluster differences were found for rates of 37 dysmorphic features (P dysmorphic features (P = 0.0001), and validating features not used in the cluster analysis: mild mental retardation (P = 0.001) and congenital heart defects (P = 0.002). Two clusters (1 and 4) appeared to represent more developmental subgroups of schizophrenia with elevated rates of dysmorphic features and validating features. Cluster 1 (n = 27) comprised mostly referred subjects. Cluster 4 (n= 18) had a different pattern of dysmorphic features; one subject had a mosaic Turner syndrome variant. Two other clusters had lower rates and patterns of features consistent with those found in previous studies of schizophrenia. Delineating patterns of dysmorphic features may help identify subgroups that could represent neurodevelopmental forms of schizophrenia with more homogeneous origins. PMID:11803519

Cortical Thinning in Network-Associated Regions in Cognitively Normal and Below-Normal Range Schizophrenia

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R. Walter Heinrichs

2017-01-01

Full Text Available This study assessed whether cortical thickness across the brain and regionally in terms of the default mode, salience, and central executive networks differentiates schizophrenia patients and healthy controls with normal range or below-normal range cognitive performance. Cognitive normality was defined using the MATRICS Consensus Cognitive Battery (MCCB composite score (T=50 ± 10 and structural magnetic resonance imaging was used to generate cortical thickness data. Whole brain analysis revealed that cognitively normal range controls (n=39 had greater cortical thickness than both cognitively normal (n=17 and below-normal range (n=49 patients. Cognitively normal controls also demonstrated greater thickness than patients in regions associated with the default mode and salience, but not central executive networks. No differences on any thickness measure were found between cognitively normal range and below-normal range controls (n=24 or between cognitively normal and below-normal range patients. In addition, structural covariance between network regions was high and similar across subgroups. Positive and negative symptom severity did not correlate with thickness values. Cortical thinning across the brain and regionally in relation to the default and salience networks may index shared aspects of the psychotic psychopathology that defines schizophrenia with no relation to cognitive impairment.

Genetic variation may explain why females are less susceptible to dental erosion.

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Uhlen, Marte-Mari; Stenhagen, Kjersti R; Dizak, Piper M; Holme, Børge; Mulic, Aida; Tveit, Anne B; Vieira, Alexandre R

2016-10-01

Not all individuals at risk for dental erosion (DE) display erosive lesions. The prevalence of DE is higher among male subjects. The occurrence of DE may depend on more than just acidic challenge, with genetics possibly playing a role. The aim of this study was to investigate the association of enamel-formation genes with DE. One premolar and a saliva sample were collected from 90 individuals. Prepared teeth were immersed in 0.01 M HCl (pH 2.2), and enamel loss (μm) was measured using white light interferometry. DNA was extracted from saliva, and 15 single-nucleotide polymorphisms were analysed. Allele and genotype frequencies were related to the enamel loss of the specimens. Single-marker and haplotype analyses were performed using sex as a covariate. Mean enamel loss was higher for male donors than for female donors (P = 0.047). Significant associations were found between enamel loss and amelogenin, X-linked (AMELX), tuftelin 1 (TUFT1), and tuftelin-interacting protein 11 (TFIP11). Analyses showed significant associations between variation in enamel-formation genes and a lower susceptibility to DE in female subjects. The results indicate that susceptibility to DE is influenced by genetic variation, and may, in part, explain why some individuals are more susceptible than others to DE, including differences between female subjects and male subjects. © 2016 Eur J Oral Sci.

American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

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Robson, Mark E; Bradbury, Angela R; Arun, Banu; Domchek, Susan M; Ford, James M; Hampel, Heather L; Lipkin, Stephen M; Syngal, Sapna; Wollins, Dana S; Lindor, Noralane M

2015-11-01

The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services. © 2015 by American Society of Clinical Oncology.

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS.

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Swerdlow, Neal R; Light, Gregory A; Sprock, Joyce; Calkins, Monica E; Green, Michael F; Greenwood, Tiffany A; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Radant, Allen D; Ray, Amrita; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2014-02-01

Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (pschizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses. Copyright © 2013 Elsevier B.V. All rights reserved.

Systematic screening for mutations in the 5{prime}-regulatory region of the human dopamine D{sub 1} receptor (DRD1) gene in patients with schizophrenia and bipolar affective disorder

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Cichon, S.; Noethen, M.M.; Stoeber, G. [Univ. of Bonn (Germany)] [and others

1996-07-26

A possible dysregulation of dopaminergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study we systematically searched for the presence of mutations in the 5{prime}-flanking region of the dopamine D{sub 1} receptor (DRD1) gene. This region has previously been shown to contain a functional promoter. We investigated 119 unrelated individuals (including 36 schizophrenic patients, 38 bipolar affective patients, and 45 healthy controls) using single-strand conformation analysis (SSCA). Eleven overlapping PCR fragments covered 2,189 bp of DNA sequence. We identified six single base substitutions: -2218T/C, -2102C/A, -2030T/C, -1992G/A, -1251G/C, and -800T/C. None of the mutations was found to be located in regions which have important influence on the level of transcriptional activity. Allele frequencies were similar in patients and controls, indicating that genetic variation in the 5{prime}-regulatory region of the DRD1 gene is unlikely to play a frequent, major role in the genetic predisposition to either schizophrenia or bipolar affective disorder. 31 refs., 3 tabs.

ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties

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St Pourcain, B; Robinson, E B; Anttila, V

2017-01-01

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic......-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34...... 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD...

Association of GSK-3β genetic variation with GSK-3β expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia.

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Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca; Di Giorgio, Annabella; Caforio, Grazia; Taurisano, Paolo; Fazio, Leonardo; Gelao, Barbara; Attrotto, Maria Teresa; Colagiorgio, Lucia; Todarello, Giovanna; Piva, Francesco; Papazacharias, Apostolos; Masellis, Rita; Mancini, Marina; Porcelli, Annamaria; Romano, Raffaella; Rampino, Antonio; Quarto, Tiziana; Giulietti, Matteo; Lipska, Barbara K; Kleinman, Joel E; Popolizio, Teresa; Weinberger, Daniel R; Usiello, Alessandro; Bertolino, Alessandro

2013-08-01

OBJECTIVE Glycogen synthase kinase 3β (GSK-3β) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3β gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3β variation is implicated in multiple phenotypes relevant to schizophrenia.

Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia.

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Hartz, Sarah M; Horton, Amy C; Oehlert, Mary; Carey, Caitlin E; Agrawal, Arpana; Bogdan, Ryan; Chen, Li-Shiun; Hancock, Dana B; Johnson, Eric O; Pato, Carlos N; Pato, Michele T; Rice, John P; Bierut, Laura J

2017-11-15

There are high levels of comorbidity between schizophrenia and substance use disorder, but little is known about the genetic etiology of this comorbidity. We tested the hypothesis that shared genetic liability contributes to the high rates of comorbidity between schizophrenia and substance use disorder. To do this, polygenic risk scores for schizophrenia derived from a large meta-analysis by the Psychiatric Genomics Consortium were computed in three substance use disorder datasets: the Collaborative Genetic Study of Nicotine Dependence (ascertained for tobacco use disorder; n = 918 cases; 988 control subjects), the Collaborative Study on the Genetics of Alcoholism (ascertained for alcohol use disorder; n = 643 cases; 384 control subjects), and the Family Study of Cocaine Dependence (ascertained for cocaine use disorder; n = 210 cases; 317 control subjects). Phenotypes were harmonized across the three datasets and standardized analyses were performed. Genome-wide genotypes were imputed to the 1000 Genomes reference panel. In each individual dataset and in the mega-analysis, strong associations were observed between any substance use disorder diagnosis and the polygenic risk score for schizophrenia (mega-analysis pseudo-R 2 range 0.8-3.7%; minimum p = 4 × 10 -23 ). These results suggest that comorbidity between schizophrenia and substance use disorder is partially attributable to shared polygenic liability. This shared liability is most consistent with a general risk for substance use disorder rather than specific risks for individual substance use disorders and adds to increasing evidence of a blurred boundary between schizophrenia and substance use disorder. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia.

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Howes, Oliver D; McCutcheon, Robert; Owen, Michael J; Murray, Robin M

2017-01-01

The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D 2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Using multivariate machine learning methods and structural MRI to classify childhood onset schizophrenia and healthy controls

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Deanna eGreenstein

2012-06-01

Full Text Available Introduction: Multivariate machine learning methods can be used to classify groups of schizophrenia patients and controls using structural magnetic resonance imaging (MRI. However, machine learning methods to date have not been extended beyond classification and contemporaneously applied in a meaningful way to clinical measures. We hypothesized that brain measures would classify groups, and that increased likelihood of being classified as a patient using regional brain measures would be positively related to illness severity, developmental delays and genetic risk. Methods: Using 74 anatomic brain MRI sub regions and Random Forest, we classified 98 COS patients and 99 age, sex, and ethnicity-matched healthy controls. We also used Random Forest to determine the likelihood of being classified as a schizophrenia patient based on MRI measures. We then explored relationships between brain-based probability of illness and symptoms, premorbid development, and presence of copy number variation associated with schizophrenia. Results: Brain regions jointly classified COS and control groups with 73.7% accuracy. Greater brain-based probability of illness was associated with worse functioning (p= 0.0004 and fewer developmental delays (p=0.02. Presence of copy number variation (CNV was associated with lower probability of being classified as schizophrenia (p=0.001. The regions that were most important in classifying groups included left temporal lobes, bilateral dorsolateral prefrontal regions, and left medial parietal lobes. Conclusions: Schizophrenia and control groups can be well classified using Random Forest and anatomic brain measures, and brain-based probability of illness has a positive relationship with illness severity and a negative relationship with developmental delays/problems and CNV-based risk.

Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness

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Ulysses S. Torres

2016-01-01

Conclusion: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

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Bradbury, Angela R; Patrick-Miller, Linda; Long, Jessica; Powers, Jacquelyn; Stopfer, Jill; Forman, Andrea; Rybak, Christina; Mattie, Kristin; Brandt, Amanda; Chambers, Rachelle; Chung, Wendy K; Churpek, Jane; Daly, Mary B; Digiovanni, Laura; Farengo-Clark, Dana; Fetzer, Dominique; Ganschow, Pamela; Grana, Generosa; Gulden, Cassandra; Hall, Michael; Kohler, Lynne; Maxwell, Kara; Merrill, Shana; Montgomery, Susan; Mueller, Rebecca; Nielsen, Sarah; Olopade, Olufunmilayo; Rainey, Kimberly; Seelaus, Christina; Nathanson, Katherine L; Domchek, Susan M

2015-06-01

Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.