Exome Sequencing in Schizophrenia-Affected Parent–offspring Trios Reveals Risk Conferred by Protein-Coding De Novo Mutations
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Rose, Samuel A.
Fromer, Menachem
Chen, Wei J.
Chambert, Kimberly
Chandler, Sharon D.
Hwu, Hai-Gwo
Moran, Jennifer L.
Faraone, Stephen V.
Glatt, Stephen J.
Tsuang, Ming
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https://doi.org/10.1038/s41593-019-0564-3Metadata
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Howrigan, Daniel P., Samuel A. Rose, Kaitlin E. Samocha, Menachem Fromer, Felecia Cerrato, Wei J. Chen, Claire Churchhouse, et al. “Exome Sequencing in Schizophrenia-Affected Parent–Offspring Trios Reveals Risk Conferred by Protein-Coding de Novo Mutations.” Nature Neuroscience 23, no. 2 (February 2020): 185–93. https://doi.org/10.1038/s41593-019-0564-3.Abstract
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.Citable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371792
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