Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas schizophrenia (SCZ) risk associated with DNMs has thus far been shown to be modest. We analyzed DNMs from 1,695 SCZ-affected trios and 1,077 published SCZ-affected trios to better understand the contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remained modest. Gene set analyses revealed that SCZ DNMs were significantly concentrated in genes that were highly expressed in the brain, that were under strong evolutionary constraint and/or overlapped with genes identified in other neurodevelopmental disorders. No single gene surpassed exome-wide significance; however, 16 genes were recurrently hit by protein-truncating DNMs, corresponding to a 3.15-fold higher rate than the mutation model expectation (permuted 95% confidence interval: 1–10 genes; permuted P = 3 × 10−5). Overall, DNMs explain a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confers risk for SCZ in the population.
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Data included in this manuscript have been deposited in the database of Genotypes and Phenotypes (dbGAP) under accession number phs001196.v1.
Data collection and analysis were not performed with blinding to the conditions of the experiments.
Code used to identify coding DNMs and assess enrichment is publicly available at https://github.com/howrigan/trio_sequence_analysis.
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This study was supported by grants from the National Human Genome Research Institute (U54 HG003067 and R01 HG006855), the Stanley Center for Psychiatric Research and the National Institute of Mental Health (R01 MH077139, R01 MH085521 and RC2 MH089905).
B.M.N. is on the Scientific Advisory Board of Deep Genomics and Camp4 Therapeutics Corporation and is on the Biogen Genomics Advisory Panel. M.F. is an employee of Verily Life Sciences.
Peer review information Nature Neuroscience thanks Ryan Yuen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Notes 1–14, Supplementary Tables 1–5 and Supplementary Figs. 1–36.
Data file descriptions.
Taiwanese cohort sample list.
Taiwanese cohort trio list.
Taiwanese cohort DNM list.
Combined cohorts DNM list.
SCZ DNM calls.
Candidate gene sets.
Candidate gene set results. Summary statistics from candidate gene set enrichment analysis.
GO + SynaptomeDB enrichment.
Recurrent PTV genes.
Recurrent PTV + missense genes.
Gene recurrence by gene set.
Predicted SCZ risk genes.
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Howrigan, D.P., Rose, S.A., Samocha, K.E. et al. Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations. Nat Neurosci 23, 185–193 (2020). https://doi.org/10.1038/s41593-019-0564-3
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