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

journal contribution
posted on 2024-11-17, 13:30 authored by Dongjing Liu, Dara Meyer, Brian Fennessy, Claudia Feng, Esther Cheng, Jessica S Johnson, You Jeong Park, Marysia Kolbe Rieder, Steven Ascolillo, Agathe de Pins, Amanda Dobbyn, Dannielle Lebovitch, Emily Moya, Tan Hoang Nguyen, Lillian Wilkins, Arsalan Hassan, Henry S Aghanwa, Moin Ansari, Aftab Asif, Rubina Aslam, Jose L Ayuso, Tim Bigdeli, Stefano Bignotti, Julio Bobes, Bekh Bradley, Peter Buckley, Murray J Cairns, Stanley V Catts, Abdul Rashid Chaudhry
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.

Funding

National Institutes of Health (B2017/BMD-3740 AGES-CM-2)

History

Journal title

Nature Genetics

Volume

55

Issue

3

Pagination

369-376

Language

English

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