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Kosmicki, Jack

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Kosmicki

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Kosmicki, Jack

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    Exome Sequencing in Schizophrenia-Affected Parent–offspring Trios Reveals Risk Conferred by Protein-Coding De Novo Mutations
    (Springer Science and Business Media LLC, 2020-01-13) Howrigan, Daniel; Rose, Samuel A.; Samocha, Kaitlin E.; Fromer, Menachem; Cerrato, Felecia; Chen, Wei J.; Churchhouse, Claire; Chambert, Kimberly; Chandler, Sharon D.; Daly, Mark; Dumont, Ashley; Genovese, Giulio; Hwu, Hai-Gwo; Laird, Nan; Kosmicki, Jack; Moran, Jennifer L.; Singh, Tarjinder; McCarroll, Steven; Faraone, Stephen V.; Glatt, Stephen J.; Tsuang, Ming; Neale, Benjamin
    Protein-coding de novo mutations (DNMs) are significant risk factors in many neurodevelopmental disorders, whereas association with schizophrenia (SCZ) risk thus far has been modest. We analyze whole-exome sequence from 1,695 SCZ affected trios along with DNMs from 1,077 published SCZ trios to better understand their contribution to SCZ risk. Among 2,772 SCZ probands, exome-wide DNM burden remains modest. Gene set analyses reveal that SCZ DNMs are significantly concentrated in genes either highly brain expressed, under strong evolutionary constraint, and/or overlap with genes identified in other neurodevelopmental disorders. No single gene surpasses exome-wide significance, however sixteen genes are recurrently hit by protein-truncating DNMs, a 3.15-fold higher rate than the mutation model expectation (permuted 95% CI=1-10 genes, permuted p=3e-5). Overall, DNMs explain only a small fraction of SCZ risk, and larger samples are needed to identify individual risk genes, as coding variation across many genes confer risk for SCZ in the population.