Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples

• Type of Material: Article
• Authors: Jack A. Kosmicki, Massachusetts General Hospital; Kaitlin E. Samocha, Massachusetts General Hospital; Daniel P. Howrigan, Massachusetts General Hospital; Stephan J. Sanders, University of California San Francisco; Kamil Slowikowski, Harvard Medical School; Monkol Lek, Massachusetts General Hospital; Konrad J. Karczewski, Massachusetts General Hospital; David Cutler, Emory University; Bernie Devlin, University of Pittsburgh; Kathryn Roeder, Carnegie Mellon University; Joseph D. Buxbaum, Icahn School of Medicine at Mount Sinai; Benjamin M. Neale, Massachusetts General Hospital; Daniel G. MacArthur, Massachusetts General Hospital; Dennis P. Wall, Stanford University; Elise B. Robinson, Massachusetts General Hospital; Mark J. Daly, Massachusetts General Hospital
• Language: English
• Date: 2017-04-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ng.3789
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 49
• Issue: 4
• Start Page: 504
• End Page: +
• Grant/Funding Information: M.L. and D.G.M.'s work on the ExAC project was funded by U54DK105566 and R01 GM104371 from the National Institutes of Health. K.S. was funded by T32 HG002295/HG/NHGRI.; E.B.R. was funded by National Institutes of Mental Health Grant 1K01MH099286 and NARSAD Young Investigator grant 22379.; This work was supported by NIH grants U01MH100233, U01MH100209, U01MH100229, and U01MH100239 to the Autism Sequencing Consortium (ASC), and R56 MH097849 and R01 MH097849 to the Population-based Autism Genetics and Environment Study (PAGES).; M.J.D., J.A.K., and K.E.S. were supported by grants from the Simons Foundation Autism Research Initiative (SFARI 342292 and a subaward from the Simons Center for the Social Brain at MIT).
• Keywords: SIBLINGS; CONGENITAL HEART-DISEASE; GENETIC RISK; RARE; GENERAL-POPULATION; AUTISM SPECTRUM DISORDERS; MUTATIONS; Science & Technology; Genetics & Heredity; INTELLECTUAL DISABILITY; Life Sciences & Biomedicine; SCHIZOPHRENIA; PATTERNS
• Research Categories: Biology, Genetics

Abstract

Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼41/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.