Rare coding variants in ten genes 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 proteintruncating 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.

Mineralocorticoid receptor and glucocorticoid receptor work alone and together in cell-type-specific manner: Implications for resilience prediction and targeted therapy

“…The GWAS Catalog however includes multiple SNP-trait associations (STAs) primarily with non-brain phenotypes ( NR3C1 : atrial fibrillation, height, lung function; NR3C2 : blood pressure, electrocardiogram morphology, lymphocyte counts; Supplementary Tables 1–2 ), but also brain phenotypes ( NR3C1 : migraine, response to ketamine, sleep; NR3C2 : Alzheimer's disease, hippocampal volume, neurofibrillary tangles; Supplementary Tables 1–2 ). Finally, rare variants in NR3C2 are associated with autism spectrum disorder ( De Rubeis et al, 2014 ; Ruzzo et al, 2019 ) and schizophrenia ( Singh et al, 2022 ). The two genes did not share many trait-associations (∼6%, Fig.…”

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients

“…Recently, the discovery of schizophrenia risk genes has been enhanced by large-scale exome or genome sequencing of tens of thousands of cases versus controls. Such studies have the power to uncover rare loss-of-function coding variants (such as protein truncating variants) that have a large impact on schizophrenia risk [1, 9, 10]. In one of the largest sequencing studies to date of 24,248 cases and 97,322 controls, the Schizophrenia Exome Sequencing Meta-analysis Consortium (SCHEMA) has identified multiple rare loss-of-function genetic variants at exome-wide level of significance that confer substantial disease risk (“SCHEMA genes”; odds ratios in the range of 4-50) [1].…”

“…Such studies have the power to uncover rare loss-of-function coding variants (such as protein truncating variants) that have a large impact on schizophrenia risk [1, 9, 10]. In one of the largest sequencing studies to date of 24,248 cases and 97,322 controls, the Schizophrenia Exome Sequencing Meta-analysis Consortium (SCHEMA) has identified multiple rare loss-of-function genetic variants at exome-wide level of significance that confer substantial disease risk (“SCHEMA genes”; odds ratios in the range of 4-50) [1]. Because these rare variants are often protein-truncating, thus presumably loss-of-function null mutations [1, 11], these disease-causing mutations can be easily modeled by genetic disruption (‘knockout’) in animals such as the mouse.…”

“… ABSTRACT

BACKGROUND Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A , encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disorder [1, 3, 4], respectively.

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“…Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A , encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disorder [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients.…”