Howrigan, DanielRose, Samuel A.Samocha, Kaitlin E.Fromer, MenachemCerrato, FeleciaChen, Wei J.Churchhouse, ClaireChambert, KimberlyChandler, Sharon D.Daly, MarkDumont, AshleyGenovese, GiulioHwu, Hai-GwoLaird, NanKosmicki, JackMoran, Jennifer L.Singh, TarjinderMcCarroll, StevenFaraone, Stephen V.Glatt, Stephen J.Tsuang, MingNeale, Benjamin2022-05-272020-01-13Howrigan, 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/s41593-019-0564-3.1097-62561546-1726https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37371792Protein-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.en-USGeneral NeuroscienceJournal Article2022-05-2710.1038/s41593-019-0564-3