Title | Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Lim, ET, Raychaudhuri, S, Sanders, SJ, Stevens, C, Sabo, A, MacArthur, DG, Neale, BM, Kirby, A, Ruderfer, DM, Fromer, M, Lek, M, Liu, L, Flannick, J, Ripke, S, Nagaswamy, U, Muzny, DM, Reid, JG, Hawes, A, Newsham, I, Wu, Y, Lewis, L, Dinh, H, Gross, S, San Wang, L-, Lin, C-F, Valladares, O, Gabriel, SB, DePristo, M, Altshuler, DM, Purcell, SM, State, MW, Boerwinkle, E, Buxbaum, JD, Cook, EH, Gibbs, RA, Schellenberg, GD, Sutcliffe, JS, Devlin, B, Roeder, K, Daly, MJ |
Corporate Authors | NHLBI Exome Sequencing Project |
Journal | Neuron |
Volume | 77 |
Issue | 2 |
Pagination | 235-42 |
Date Published | 2013 Jan 23 |
ISSN | 1097-4199 |
Keywords | Case-Control Studies, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, X, Demography, Female, Gene Deletion, Genetic Variation, Homozygote, Humans, Linkage Disequilibrium, Loss of Heterozygosity, Male, Risk Factors |
Abstract | To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD. |
DOI | 10.1016/j.neuron.2012.12.029 |
Alternate Journal | Neuron |
PubMed ID | 23352160 |
PubMed Central ID | PMC3613849 |
Grant List | U24 MH081810 / MH / NIMH NIH HHS / United States R37 MH057881 / MH / NIMH NIH HHS / United States R01 MH089004 / MH / NIMH NIH HHS / United States R01 MH057881 / MH / NIMH NIH HHS / United States HL-102924 / HL / NHLBI NIH HHS / United States RC2 HL102924 / HL / NHLBI NIH HHS / United States U24 MH068457 / MH / NIMH NIH HHS / United States HL-102925 / HL / NHLBI NIH HHS / United States RC2 HL103010 / HL / NHLBI NIH HHS / United States R01 MH089482 / MH / NIMH NIH HHS / United States RC2 HL102923 / HL / NHLBI NIH HHS / United States UC2 HL102926 / HL / NHLBI NIH HHS / United States R01 MH089208 / MH / NIMH NIH HHS / United States UC2 HL103010 / HL / NHLBI NIH HHS / United States HL-103010 / HL / NHLBI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States P50HD055751 / HD / NICHD NIH HHS / United States RC2 HL102926 / HL / NHLBI NIH HHS / United States R01 MH061009 / MH / NIMH NIH HHS / United States U24MH068457 / MH / NIMH NIH HHS / United States 1U24MH081810 / MH / NIMH NIH HHS / United States R01MH061009 / MH / NIMH NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01MH089175 / MH / NIMH NIH HHS / United States P50 HD055751 / HD / NICHD NIH HHS / United States HL-102926 / HL / NHLBI NIH HHS / United States R01 MH089025 / MH / NIMH NIH HHS / United States R01MH089004 / MH / NIMH NIH HHS / United States R01MH089208 / MH / NIMH NIH HHS / United States R01 MH089175 / MH / NIMH NIH HHS / United States R01MH057881 / MH / NIMH NIH HHS / United States UC2 HL102923 / HL / NHLBI NIH HHS / United States UC2 HL102924 / HL / NHLBI NIH HHS / United States HL-102923 / HL / NHLBI NIH HHS / United States R01MH089025 / MH / NIMH NIH HHS / United States R01MH089482 / MH / NIMH NIH HHS / United States RC2 HL102925 / HL / NHLBI NIH HHS / United States UC2 HL102925 / HL / NHLBI NIH HHS / United States |
Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.
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