Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations

Abstract

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes¹. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10^-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.

Fig. 1. Study design and cohort ancestry composition.

a, Overview of the study design. b, Gene selection for the targeted sequencing panel. Genes were selected based on a combination of previous association statistics (SCHEMA), gTADA rankings and GWAS associations. Specially, we included: (1) genes in the top 100 based on the gTADA rank and/or the SCHEMA P value (top 100 in SCHEMA and gTADA, top 100 in SCHEMA alone and top 100 in gTADA alone; total n = 133 genes); (2) genes with evidence for association with SCZ in both GWASs and SCHEMA (special GWAS genes; n = 4 genes); and (3) an additional 24 genes that had the best 24 gTADA rankings of the remaining genes with a burden P value of <0.05, to fill up the target panel. The x axis shows the gene-level P value using SCHEMA interim data, based on which the panel was constructed (different from the final published version). The y axis shows the gTADA rank of genes. Only the top 500 genes are plotted for a clear display. Some highly ranked genes were excluded (gray dots) due to logistic issues during panel construction. c, PGC3SEQ ancestry composition. PGC3SEQ samples include substantial non-EUR ancestry. The first two principal components (PCs) are plotted along each axis, colored by SCZ case versus control status. 1000 Genomes samples are colored by super-population.

Fig. 2. Global enrichment in 80 panel genes under strong constraint (pLI > 0.9).

a, Case–control enrichment of rare (minor allele count ≤ 5) protein-truncating, missense and synonymous variants in all ancestries combined. The PGC3SEQ results were derived from 11,580 individuals with SCZ and 10,555 controls and are shown in red/orange. We conducted the same analysis in the SCHEMA samples (shown in gray; 19,108 cases and 18,001 controls) that we had access to for comparison. b, Ancestry-stratified rare variant (MAF < 0.1%) enrichment in the meta-analysis of PGC3SEQ and SCHEMA (29,381 cases and 27,942 controls). Three groups of variants were analyzed: PTV + MPC > 3 missense variants (combined to increase the power); MPC = 2–3 missense variants; and synonymous variants. The data are presented as point estimates of enrichment ORs (dots) and 95% confidence intervals (bars). Two-sided P values were calculated using Firth logistic regression, controlling for five ancestry principal components and either the rare synonymous variant count (for PTV and missense variants) or the rare nonsynonymous variant count (for synonymous variants), to control for potential unknown technical biases.