Exome sequencing identifies rare coding variants in 10 genes which confer substantial risk for schizophrenia

Abstract

By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 - 50, P < 2.14 x 10^-6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We find significant evidence for an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD), and severe neurodevelopmental disorders (DD/ID), supporting a neurodevelopmental etiology for schizophrenia. We show that protein-truncating variants in GRIN2A, TRIO, and CACNA1G confer risk for schizophrenia whereas specific missense mutations in these genes confer risk for DD/ID. Nevertheless, few of the strongly associated schizophrenia genes appear to confer risk for DD/ID. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more schizophrenia risk genes await discovery using this approach.

Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia

“…This enrichment is consistent among both BD1 and BD2 subtypes (Figure 1A). While the magnitude of PTV enrichment in BD (OR = 1.11, P = 5.0 × 10 −5 ) is considerably lower than the latest PTV enrichment in schizophrenia (OR = 1.26; ( 19 )), this difference is in line with the increased selective pressure estimated from higher reproductive rates in BD affected siblings relative to those seen in schizophrenia affected siblings ( 8 ).…”

“…Following this initial restriction we observed nominally significant enrichment of damaging missense variation in BD cases and BD2 cases over controls (OR = 1.01, P = 0.024 and OR = 1.02, P = 0.0086 respectively); Figure 1B,C, but not for the other a priori damaging classes of variation (missense MPC > 2, and PTV). However, stepwise filtering of rare PTVs to those not in the non-psychiatric portion of the Genome Aggregation Database (gnomAD), hereafter referred to as ‘ultra-rare variants’, and then in constrained genes (defined as p LI ≥ 0.9), shows that case-control PTV enrichment is present once we filter to high p LI genes, a finding in line with schizophrenia exomes ( 19 ); Figure 1B,C. This enrichment is consistent among both BD1 and BD2 subtypes (Figure 1A).…”

DLG2 knockout reveals neurogenic transcriptional programs underlying neuropsychiatric disorders and cognition

“… a , Summary of main GO term enrichments for each transcriptional program (Supplementary Table 5) and identified regulatory interactions between them. Key regulators, genome-wide significant rare coding variants from 79 and rare mutations causing Mendelian neurodevelopmental syndromes are denoted. b , Neurodevelopmental continuum/gradient model.…”

Analyses of GWAS and sub-threshold loci lead to the discovery of dendrite development and morphology dysfunction underlying schizophrenia genetic risk

“…We sought to probe whether rare coding variants in genes in DD and DM are also associated with SCZ risk. We collected rare variant association summary statistics data at gene level from SCHEMA (https://schema.broadinstitute.org/) (Singh et al, 2020) and observed that genes of DD and DM sets have signi cantly smaller P-values than random background genes (P DD = 8.55 x 10 -6 , P DM = 1.62 x 10 -4 , SF 15; Wilcoxon test). After removing allHRGs from GO terms, the P values of the remaining genes remain signi cant (P DD = 7.03 x 10 -5 , P DM = 5.67 x 10 -4 , SF 15; Wilcoxon test).Rare coding variants in genes in dendrite development and morphogenesis are associated with SCZ Genes in dendrite development and morphogenesis terms show speci city in neurons at fetal and adult stages A current neuropathology model of SCZ is a revised neurodevelopment hypothesis proposing the contribution of neurodevelopmental processes at both early (pre-or perinatal stages) and late (childhood to adolescence) stages (Gogtay et al, 2011).…”