Genome-Wide Association Study of Clinical Dimensions of Schizophrenia: Polygenic Effect on Disorganized Symptoms

Abstract

Objective 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. Method Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. Results No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/ disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. Conclusions The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Most recent evidence supports a combination of genetic and environmental factors contributing to the development of the disorder (Marenco and Weinberger, 2000). To date, no one gene, single-nucleotide polymorphism, or mutation has been consistently linked to the illness, and it is likely that multiple susceptibility genes create a predisposition to developing schizophrenia (Fanous et al, 2012;Gershon et al, 2011;Levinson et al, 2012). Genetics studies, which have led the way for diseases such as breast cancer and cystic fibrosis, have been much less impactful in the schizophrenia field.…”

“…A recent genome-wide association study (GWAS) of B2500 subjects with B700 000 single-nucleotide polymorphisms (SNPs) looked at the relationship between genetic markers and three dimensions, positive, negative/ disorganized, and mood, and concluded that schizophrenia is polygenic (Fanous et al, 2012). Another genome-wide analysis identified four SNPs across five disorders in 430 000 patients and B30 000 controls, which reached genome-wide significance, suggesting that severe mental illnesses such as schizophrenia, bipolar disorder, and depression share common polygenic risk factors (Smoller et al, 2013).…”

Update: Negativsymptome. Psychopathologie, Epidemiologie, Pathophysiologie und Behandlungsoptionen.

“…Im Rahmen von genomweiten Assoziationsstudien wurden genetische Polymorphismen mit den klinischen Dimensionen der Negativsymptome in Verbindung gebracht [62], polygenetische Signale scheinen mit Faktoren für Desorganisation und Negativsymptome zu korrelieren [62]. Ein Polymorphismus der Catechol-O-Methyltransferase (COMT) -einem Enzym des zerebralen Dopaminstoffwechels -wird mit einer stärke-ren Ausprägung von Negativsymptomen assoziiert [63,64].…”

Genes and Schizophrenia: From a Festschrift Seminar Honoring William T. Carpenter Jr, MD

“…Moreover, larger scale efforts are now underway to assess the contribution of specific genetic factors to key symptom domains. 30 The PGC is amassing data from thousands of subjects with more refined symptomatic assessments to conduct a comprehensive genome-wide analysis of symptom domains including negative symptoms. Finally, relatively large-scale studies within academia and the Veterans Administration system 31 are focusing their efforts on the identification of genes that influence functional disability and may further highlight the important role of genes that influence negative symptom severity.…”