Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

Allen, Nicole C.; Bagade, Sachin; McQueen, Matthew B.; Ioannidis, John P. A.; Kavvoura, Fotini K.; Khoury, Muin J.; Tanzi, Rudolph E.; Bertram, Lars

doi:10.1038/ng.171

Cited by 964 publications

(802 citation statements)

References 39 publications

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“…To our knowledge, the 8p23.3-p23.1 deletion and 19p13.3-p13.2 duplication have not been previously reported. There are other chromosomal abnormalities associated with schizophrenia that involve these regions (Bassett et al, 2000); however, there is no direct overlap with linkage or "top" association findings highlighted in the January 2010 SzGene Database (Allen et al, 2008). There are 11 genes in the 8p23.3-p23.1 region and approximately 250 genes in the 19p13.3-p13.2 region.…”

Section: Discussionmentioning

confidence: 99%

Clinically detectable copy number variations in a Canadian catchment population of schizophrenia

Bassett

Costain

Fung

et al. 2010

Journal of Psychiatric Research

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Copy number variation (CNV) is a highly topical area of research in schizophrenia, but the clinical relevance is uncertain and the translation to clinical practice is under-studied. There is a paucity of research involving truly community-based samples of schizophrenia and widely available laboratory techniques. Our objective was to determine the prevalence of clinically detectable CNVs in a community sample of schizophrenia, while mimicking typical clinical practice conditions. We used a brief clinical screening protocol for developmental features in adults with schizophrenia for identifying individuals with 22q11.2 deletions and karyotypically detectable chromosomal anomalies in 204 consecutive patients with schizophrenia from a single Canadian catchment area. Twenty-seven (13.2%) subjects met clinical criteria for a possible syndrome, and 26 of these individuals received clinical genetic testing. Five of these, representing 2.5% of the total sample (95% CI: 0.3%-4.6%), including two of ten patients with mental retardation, had clinically detectable anomalies: two 22q11.2 deletions (1.0%), one 47, XYY, and two other novel CNVs -an 8p23.3-p23.1 deletion and a de novo 19p13.3-p13.2 duplication. The results support the utility of screening and genetic testing to identify genetic syndromes in adults with schizophrenia in clinical practice. Identifying large, rare CNVs (particularly 22q11.2 deletions) can lead to significant changes in management, follow-up, and genetic counselling that are helpful to the patient, family, and clinicians.

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Section: Discussionmentioning

confidence: 99%

Clinically detectable copy number variations in a Canadian catchment population of schizophrenia

Bassett

Costain

Fung

et al. 2010

Journal of Psychiatric Research

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“…26 Within SLC6A4, STin2 has been reported to be the strongest candidate polymorphism showing susceptibility to schizophrenia. 17,27 The STin 2.12 allele has been reported to have increased vulnerability to schizophrenia. [28][29][30][31] These observations are consistent with current results.…”

Section: Discussionmentioning

confidence: 99%

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

et al. 2009

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Serotonin (5-hydroxytryptamine (5-HT)) transporter (SLC6A4) is known to influence mood, emotion, cognition and efficacy of antidepressants, particularly that of selective serotonin reuptake inhibitors. Atypical antipsychotics exert their effects partially through serotinergic systems, and hence, variation in 5-HT uptake may affect antipsychotic action mediated through the serotinergic system. Therefore, investigating the role of SLC6A4 as a risk factor for developing schizophrenia and treatment response had been a point of concern for many investigators, but with variable outcome. In this study, we examined the genetic roles of five polymorphisms of SLC6A4, including those of the widely studied 44 base pair variable number of tandem repeat (VNTR) in the promoter region of SLC6A4 (the serotonin transporter gene-linked polymorphic region: 5HTTLPR) and a VNTR polymorphism (STin2) in the second intron, in schizophrenia and its influence on the severity of symptoms in a South Indian population from Kerala, comprising 586 individuals. We detected significant allelic and genotypic associations with rs2066713 (both allelic and genotypic P-value o0.001), 5HTTLPR (allelic P-value¼0.008 and genotypic P-value¼0.03) and STin2 polymorphisms (allelic P-value¼0.001 and genotypic P-value¼0.002). A haplotype linking these three risk alleles, 5HTTLPR/ S-rs2066713/C-STin2/12-repeat (P-value¼0.0059), was also significantly associated with disease in our population. Patients with STin2 12-repeat homozygotes showed a greater severity of blunted effect symptom. These results suggest a strong role of SLC6A4 in schizophrenia, possibly with a specific behavioral endophenotype in a South Indian population. Keywords: case-control; SLC6A4; schizophrenia; South India; symptom profile INTRODUCTION Schizophrenia is a common and complex psychiatric disorder, with proven genetic causes. Research to unravel the genetic basis of schizophrenia has revealed several molecules, including those involved in dopamine and serotonin neurotransmitter systems for the past few decades. Serotonin (5-hydroxytryptamine (5-HT)) hypothesis of schizophrenia has been reanalyzed with the effectiveness of clozapine, the best known atypical antipsychotic drug, 1 as an antagonist for several 5-HT receptors. 2,3 Moreover, 5-HT has been shown to regulate the development of the central nervous system. As the 5-HT transporter (5-HTT) regulates the 5-HT system, 4 alterations in the function of this protein could be involved in the development of schizophrenia. 5 The serotonin transporter (SLC6A4) gene spanning 37.8 kb is located on chromosome 17q11.2, 6,7 and has 14 exons encoding a protein of 630 amino acids. 8 SLC6A4 has received attention as a candidate in schizophrenia and mood disorders, owing to its influence on mood, emotion, cognition and also because 5-HTT is the principal site of action for some antidepressants, particularly for the selective

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“…Ever since the mapping of the human genome, identification of genetic determinants of complex psychiatric disorders such as schizophrenia, major depression or bipolar disorder has proven challenging (Allen et al., 2008). Indeed, genome‐wide association studies (GWAS) have shown that these disorders are highly polygenic (Barnett & Smoller, 2009; Schizophrenia Working Group of the Psychiatric Genomics, 2014; Shyn et al., 2011) with many genes exerting their influence on numerous neural pathways involved in complex aspects of brain function and likely being impacted upon by environmental events.…”

Section: Introductionmentioning

confidence: 99%

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

et al. 2017

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IntroductionPrevious research has indicated that variation in genes encoding catechol‐O‐methyltransferase (COMT) and dopamine receptor D2 (DRD2) may influence cognitive function and that this may confer vulnerability to the development of mental health disorders such as schizophrenia. However, increasing evidence suggests environmental factors such as early life stress may interact with genetic variants in affecting these cognitive outcomes. This study investigated the effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress in healthy adults.MethodsOne hundred and twenty‐two healthy adult males (mean age 35.2 years, range 21–63) were enrolled in the study. Cognitive function was assessed using Cambridge Neuropsychological Test Automated Battery and early life stress was assessed using the Childhood Traumatic Events Scale (Pennebaker & Susman, 1988).Results DRD2 C957T was significantly associated with executive function, with CC homozygotes having significantly reduced performance in spatial working memory and spatial planning. A significant genotype–trauma interaction was found in Rapid Visual Information Processing test, a measure of sustained attention, with CC carriers who had experienced early life stress exhibiting impaired performance compared to the CC carriers without early life stressful experiences. There were no significant findings for COMT Val158Met.ConclusionsThis study supports previous findings that DRD2 C957T significantly affects performance on executive function related tasks in healthy individuals and shows for the first time that some of these effects may be mediated through the impact of childhood traumatic events. Future work should aim to clarify further the effect of stress on neuronal systems that are known to be vulnerable in mental health disorders and more specifically what the impact of this might be on cognitive function.

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Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database

Cited by 964 publications

References 39 publications

Clinically detectable copy number variations in a Canadian catchment population of schizophrenia

Clinically detectable copy number variations in a Canadian catchment population of schizophrenia

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population

The effect of COMT Val158Met and DRD2 C957T polymorphisms on executive function and the impact of early life stress

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