@article{64b9af0377884297ac1c1e1fa97ddb28,
title = "Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders",
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.",
author = "Lim, {Elaine T.} and Soumya Raychaudhuri and Sanders, {Stephan J.} and Christine Stevens and Aniko Sabo and MacArthur, {Daniel G.} and Neale, {Benjamin M.} and Andrew Kirby and Ruderfer, {Douglas M.} and Menachem Fromer and Monkol Lek and Li Liu and Jason Flannick and Stephan Ripke and Uma Nagaswamy and Donna Muzny and Reid, {Jeffrey G.} and Alicia Hawes and Irene Newsham and Yuanqing Wu and Lora Lewis and Huyen Dinh and Shannon Gross and Wang, {Li San} and Lin, {Chiao Feng} and Otto Valladares and Gabriel, {Stacey B.} and Mark dePristo and Altshuler, {David M.} and Purcell, {Shaun M.} and State, {Matthew W.} and Eric Boerwinkle and Buxbaum, {Joseph D.} and Cook, {Edwin H.} and Gibbs, {Richard A.} and Schellenberg, {Gerard D.} and Sutcliffe, {James S.} and Bernie Devlin and Kathryn Roeder and Daly, {Mark J.}",
note = "Funding Information: We gratefully acknowledge the following resources and families who contributed to them: the National Institute of Mental Health (NIMH) repository (U24MH068457); Autism Genetic Resource Exchange (AGRE) Consortium, a program of Autism Speaks (1U24MH081810 to Clara M. Lajonchere); The Autism Simplex Collection (TASC) (grant from Autism Speaks); Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (grant from the Simons Foundation); The Autism Consortium (grant from the Autism Consortium). For full citation of resources, please see Supplemental Information . This work was directly supported by NIH grants R01MH089208 (M.J.D.), R01MH089025 (J.D.B.), R01MH089004 (G.D.S.), R01MH089175 (R.A.G.), and R01MH089482 (J.S.S.) and supported in part by NIH grants P50HD055751 (E.H.C.), R01MH057881 (B.D.), and R01MH061009 (J.S.S.). We acknowledge partial support from U54 HG003273 (R.A.G.) and U54 HG003067 (E. Lander). We thank Thomas Lehner (NIMH), Adam Felsenfeld (NHGRI), and Patrick Bender (NIMH) for their support and contribution to the project. E.B., J.D.B., B.D., M.J.D., R.A.G., K.R., A.S., G.D.S., and J.S.S. are lead investigators in the ARRA Autism Sequencing Collaboration (AASC). We would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies that produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926), and the Heart GO Sequencing Project (HL-103010). ",
year = "2013",
month = jan,
day = "23",
doi = "10.1016/j.neuron.2012.12.029",
language = "English (US)",
volume = "77",
pages = "235--242",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "2",
}