Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

Disrupted‐in‐schizophrenia 1 overexpression disrupts hippocampal coding and oscillatory synchronization

“…Chronic mental illnesses (CMI), such as schizophrenia and recurrent affective disorders, are highly heritable and have been associated with a large number of genetic loci (Schizophrenia Working Group of the Psychiatric Genomics Consortium, ). However, there is agreement that not all causes of CMI are heritable, indicating that the pathophysiology underlying CMI is complex and also involves nongenetic factors (Pardiñas et al, ). Albeit still a niche in psychiatry research, there is increasing evidence that aberrant protein homeostasis and resulting aggregation may be a nongenetic cause for developing CMI (Bradshaw & Korth, ).…”

Transcriptional Changes following Cellular Knockdown of the Schizophrenia Risk Gene <b><i>SETD1A</i></b> Are Enriched for Common Variant Association with the Disorder

“…We therefore tested for enrichment of schizophrenia association signal in genes differentially expressed following SETD1A knockdown using summary statistics from the largest schizophrenia GWAS published to date [19]. Genes that were differentially expressed in association with both SETD1A siRNA conditions were enriched for schizophrenia association using either the default of all protein-coding genes as the background comparison ( p = 0.016) or all genes expressed in the tested SH-SY5Y cells ( p = 0.036).…”

“…MAGMA performs tests of competitive gene set enrichment using summary results from GWAS, controlling for confounders such as gene size, gene density and linkage disequilibrium. We tested for enrichment of schizophrenia common variant signal using summary data from a recent schizophrenia GWAS containing a total of 105,318 participants [19]. A window of 10 kb around each gene was included for single-nucleotide polymorphism annotations.…”

Targeted Sequencing of 10,198 Samples Confirms Abnormalities in Neuronal Activity and Implicates Voltage-Gated Sodium Channels in Schizophrenia Pathogenesis

“…A major limiting factor, as for studies of common variants, is that for complex disorders, large samples are required to obtain robust results in case-control studies (13). To date, the largest published sequencing studies of schizophrenia have involved around 5000 cases, 9000 controls, and 1000 parent-proband trios 7, 11, almost an order of magnitude smaller than recently published schizophrenia single nucleotide polymorphism genotyping studies of common risk variants [e.g., 40,675 cases and 64,643 controls (4)]. Nevertheless, exome sequencing studies have provided important clues to the pathophysiology of schizophrenia.…”