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

Psychiatric Genomics Consortium Phase 3 Targeted Sequencing of Schizophrenia Study Team

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)369-376
Number of pages8
JournalNature Genetics
Volume55
Issue number3
DOIs
StatePublished - Mar 2023
Externally publishedYes

Funding

FundersFunder number
Fundación Familia Alonso
Takeda Pharmaceuticals U.S.A.
European Commission
Neuroscience Research Australia
Ministero della Salute
F. Hoffmann-La Roche
European Regional Development Fund/European Social Fund A Way
European Regional Development Fund
Australian Schizophrenia Research Bank
Horizon 2020
Centro de Investigación Biomédica en Red de Salud Mental, Madrid Regional GovernmentB2017/BMD-3740 AGES-CM-2
National Health and Medical Research Council1176716, 513861, 1037196, 1063960
Cardiff UniversityR01MH100125, P50MH066392, 1R01MH124851, 1I01CX000995
Horizon 2020 Framework Programme777394
Medical Research Council CentreMR/L010305/1
National Institutes of HealthR01MH093725, ZIC MH002903, R01MH085542, P50MH080405, U01MH103392, AG02219, R37MH057881, R01MH097276, AG05138, MH06692, HHSN271201300031C, R01AG050986, R01MH110921, R01AG065582, P50MH084053S1, R01AG067025, RO1MH-075916, R01MH109897, R01MH109677, P50M096891, R01MH106056, R01MH125246, U01MH116442
Fundación Alicia KoplowitzCPII21/00008, MS16/00153, PI18/00213
Spanish Ministry of Science and Innovation Instituto de Salud Carlos IIIPI19/024
National Institute of Mental HealthR01MH124839, U01MH109536, R01MH118278
Innovative Medicines Initiative115916, AIMS-2-TRIALS
UK Research and InnovationMR/P005748/1
Centro de Investigación Biomédica en Red de Salud MentalCD20/00118
Instituto de Salud Carlos IIIPI18/00238, PI18/00467

    Fingerprint

    Dive into the research topics of 'Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations'. Together they form a unique fingerprint.

    Cite this