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Neuron DOI:10.1016/j.neuron.2012.12.029

Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

Publication TypeJournal Article
Year of Publication2013
AuthorsLim, 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, D, 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 AuthorsNHLBI Exome Sequencing Project
JournalNeuron
Volume77
Issue2
Pages235-42
Date Published2013 Jan 23
ISSN1097-4199
KeywordsCase-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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0896-6273(13)00033-0
DOI10.1016/j.neuron.2012.12.029
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23352160?dopt=Abstract

Alternate JournalNeuron
PubMed ID23352160
PubMed Central IDPMC3613849
Grant ListU24 MH081810 / 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
R37 MH057881 / MH / NIMH 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 MH089004 / MH / NIMH 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
R01 MH057881 / MH / NIMH NIH HHS / United States
HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI 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
U24 MH068457 / 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-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / 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
R01 MH089482 / MH / NIMH NIH HHS / United States