Exome sequencing in schizophrenia-affected parent–offspring trios reveals risk conferred by protein-coding de novo mutations
Journal
Nature Neuroscience
Journal Volume
23
Journal Issue
2
Pages
185-193
Date Issued
2020
Author(s)
Howrigan D.P.
Rose S.A.
Samocha K.E.
Fromer M.
Cerrato F.
Churchhouse C.
Chambert K.
Chandler S.D.
Daly M.J.
Dumont A.
Genovese 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.
Abstract
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. ? 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
SDGs
Other Subjects
adult; Article; autism; controlled study; developmental delay; DNA barcoding; female; gene expression; gene mutation; genetic association; genetic variation; human; intellectual impairment; major clinical study; male; parent; priority journal; progeny; protein coding de novo mutation; risk assessment; schizophrenia; synapse; Taiwan; Taiwanese; whole exome sequencing; child; child parent relation; family; genetic predisposition; genetics; mutation; schizophrenia; whole exome sequencing; Adult; Child; Family; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Parents; Schizophrenia; Whole Exome Sequencing
Type
journal article