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.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Howrigan DP,Rose SA,Samocha KE,Fromer M,Cerrato F,Chen WJ,Churchhouse C,Chambert K,Chandler SD,Daly MJ,Dumont A,Genovese G,Hwu HG,Laird N,Kosmicki JA,Moran JL,Roe C,Singh T,Wang SH,Faraone SV,Glatt SJ,McCarrolldoi
10.1038/s41593-019-0564-3subject
Has Abstractpub_date
2020-02-01 00:00:00pages
185-193issue
2eissn
1097-6256issn
1546-1726pii
10.1038/s41593-019-0564-3journal_volume
23pub_type
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