Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations
Open accessAbstract
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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Earlier sequencing studies established that ultra-rare and de novo mutations contribute to schizophrenia risk and found enrichment in neuronal genes and synaptic processes.
“Earlier schizophrenia sequencing studies have established that ultra-rare and de novo mutations contribute to risk as a category, and have prioritized disease-relevant tissues and processes, specifically observing an enrichment in neuronal genes and synaptic processes9,11,19–23.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [21]
URV analysis has had limited success in individual gene discovery for schizophrenia due to power limitations, with only SETD1A robustly associated.
“However, the analysis of URVs has had limited success in delivering individual gene discovery in schizophrenia because of power limitations, with only a single gene, SETD1A, identified as robustly associated16,21.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [21]
The SETD1A de novo PTV finding supports the earlier report that SETD1A is associated with both schizophrenia and broader neurodevelopmental disorders.
“supporting an earlier report that described SETD1A as a gene associated with both schizophrenia and broader neurodevelopmental disorders21.”
From Rare coding variants in ten genes confer substantial risk for schizophrenia (2022) · cites this paper as [21]
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References 53 · Cited by 168
Research works printed but not linked: 1
- [34]Karczewski KJFLCTG, Cummings BB; Alföldi J; Wang Q; Collins RL, Laricchia KM; Ganna A; Birnbaum DP; Gauthier Laura D, Brand Harrison, Solomonson Matthew, Watts Nicholas A, Rhodes Daniel, Singer-Berk Moriel, Seaby Eleanor G, Kosmicki Jack A, Walters Raymond K, Tashman Katherine, Farjoun Yossi, Banks Eric, Poterba Timothy, Wang Arcturus, Seed Cotton, Whiffin Nicola, Chong Jessica X, Samocha Kaitlin E, Pierce-Hoffman Emma, Zappala Zachary, O’Donnell-Luria Anne H, Minikel Eric Vallabh, Weisburd Ben, Lek Monkol, Ware James S, Vittal Christopher, Armean Irina M, Bergelson Louis, Cibulskis Kristian, Connolly Kristen M, Covarrubias Miguel, Donnelly Stacey, Ferriera Steven, Gabriel Stacey, Gentry Jeff, Gupta Namrata, Jeandet Thibault, Kaplan Diane, Llanwarne Christopher, Munshi Ruchi, Novod Sam, Petrillo Nikelle, Roazen David, Ruano-Rubio Valentin, Saltzman Andrea, Schleicher Molly, Soto Jose, Tibbetts Kathleen, Tolonen Charlotte, Wade Gordon, Talkowski Michael E, The Genome Aggregation Database Consortium, Neale Benjamin M, Daly Mark J, MacArthur Daniel G, Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes. BioRxiv, 2019.
- Authors
- Howrigan, D. P., Rose, S. A., Samocha, K. E., Fromer, M., Cerrato, F., Chen, W. J., Churchhouse, C., Chambert, K., Chandler, S. D., Daly, M. J., Dumont, A., Genovese, G., Hwu, H.-G., Laird, N., Kosmicki, J. A., Moran, J. L., Roe, C., Singh, T., Wang, S.-H., Faraone, S. V., Glatt, S. J., McCarroll, S. A., Tsuang, M., & Neale, B. M.
- Affiliations
- Broad Institute (US)
- National Taiwan University (TW)
- University of California San Diego (US)
- Harvard University (US)
- SUNY Upstate Medical University (US)
- China Medical University (TW)
- Corresponding author
- Howrigan, Daniel P.
- Neale, Benjamin M.
- ORCID
- Howrigan, Daniel P.
- Rose, Samuel A.
- Samocha, Kaitlin E.
- Fromer, Menachem
- Cerrato, Felecia
- Chen, Wei J.
- Churchhouse, Claire
- Daly, Mark J.
- Genovese, Giulio
- Hwu, Hai-Gwo
- Laird, Nan
- Kosmicki, Jack A.
- Moran, Jennifer L.
- Singh, Tarjinder
- Wang, Shi-Heng
- Faraone, Stephen V.
- Glatt, Stephen J.
- McCarroll, Steven A.
- Tsuang, Ming
- Neale, Benjamin M.
- Venue
- Nature Neuroscience
- Published
- 2020-01-13
- Volume
- 23
- Issue
- 2
- Pages
- 185-193
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7007385
- OpenAlex
- W2998914148
- Cited by
- 168
- References
- 53
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 29 · 2023: 29 · 2022: 34 · 2021: 27 · 2020: 19 · 2019: 2
- FWCI
- 20.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (R01 HG006855)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01 MH077139, R01 MH085521, RC2 MH089905)
- Broad Institute | Stanley Center for Psychiatric Research, Broad Institute
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- schizophrenia, de novo mutations, parent-offspring trios, exome sequencing, neurodevelopmental disorders, brain-expressed genes, negative selection, recurrent mutations, genetic risk
- MeSH terms
- Exome Sequencing, Adult, Child, Family, Female, Humans, Male, Mutation, Parents, Schizophrenia, Genetic Predisposition to Disease
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