Integrated Post-GWAS Analysis Sheds New Light on the Disease Mechanisms of Schizophrenia

Abstract

Schizophrenia is a severe mental disorder with a large genetic component. Recent genome-wide association studies (GWAS) have identified many schizophrenia-associated common variants. For most of the reported associations, however, the underlying biological mechanisms are not clear. The critical first step for their elucidation is to identify the most likely disease genes as the source of the association signals. Here, we describe a general computational framework of post-GWAS analysis for complex disease gene prioritization. We identify 132 putative schizophrenia risk genes in 76 risk regions spanning 120 schizophrenia-associated common variants, 78 of which have not been recognized as schizophrenia disease genes by previous GWAS. Even more significantly, 29 of them are outside the risk regions, likely under regulation of transcriptional regulatory elements contained therein. These putative schizophrenia risk genes are transcriptionally active in both brain and the immune system, and highly enriched among cellular pathways, consistent with leading pathophysiological hypotheses about the pathogenesis of schizophrenia. With their involvement in distinct biological processes, these putative schizophrenia risk genes, with different association strengths, show distinctive temporal expression patterns, and play specific biological roles during brain development.

Genetic overlap between psychotic experiences in the community across age and with psychiatric disorders

“…Six mapped genes overlapped between adult schizotypy and psychiatric disorders, including ANK3 discussed above. As noted elsewhere (20), we found evidence that CACNA1C on band 12pl3.33, a gene that has often been associated with psychiatric and developmental disorders (39, 59, 60, 67, 68), may be involved in hypomania, schizophrenia and bipolar disorder. Located within the same region as CACNA1C (12p13.33), the genes DCP1B, TSPAN9 and FKBP4 also overlapped between hypomania and schizophrenia and have previously been associated with a range of physical health phenotypes including obesity and waist-hip ratio (65, 69).…”

A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium

“…93 This method is to be applied in the IBBC WGS analyses. Other upcoming IBBC publications include findings on novel structural polymorphisms that predispose to chromosome 22q11.2 rearrangements, and analysis of the extent to which schizophrenia polygenic risk score predicts outcome in 22q11DS.…”

An integration analysis based on genomic, transcriptomic and QTX information reveals credible candidate genes for fat‐related traits in pigs

“…2014; Lin et al . 2016). However, compared with QTL mapping or GWAS with little information, the integration analysis contains more proximal regulatory genes, and this may indicate that, as the information increases, many distal candidate genes will be redefined as proximal candidate genes and integration analysis may be more accurate in mapping causal genes.…”