Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

Elaine T. Lim; Soumya Raychaudhuri; Stephan J. Sanders; Christine Stevens; Aniko Sabo; Daniel G. MacArthur; Benjamin M. Neale; Andrew Kirby; Douglas M. Ruderfer; Menachem Fromer; Monkol Lek; Li Liu; Jason Flannick; Stephan Ripke; Uma Nagaswamy; Donna Muzny; Jeffrey G. Reid; Alicia Hawes; Irene Newsham; Yuanqing Wu; Lora Lewis; Huyen Dinh; Shannon Gross; Li San Wang; Chiao Feng Lin; Otto Valladares; Stacey B. Gabriel; Mark dePristo; David M. Altshuler; Shaun M. Purcell; Matthew W. State; Eric Boerwinkle; Joseph D. Buxbaum; Edwin H. Cook; Richard A. Gibbs; Gerard D. Schellenberg; James S. Sutcliffe; Bernie Devlin; Kathryn Roeder; Mark J. Daly

doi:10.1016/j.neuron.2012.12.029

Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

Elaine T. Lim, Soumya Raychaudhuri, Stephan J. Sanders, Christine Stevens, Aniko Sabo, Daniel G. MacArthur, Benjamin M. Neale, Andrew Kirby, Douglas M. Ruderfer, Menachem Fromer, Monkol Lek, Li Liu, Jason Flannick, Stephan Ripke, Uma Nagaswamy, Donna Muzny, Jeffrey G. Reid, Alicia Hawes, Irene Newsham, Yuanqing WuLora Lewis, Huyen Dinh, Shannon Gross, Li San Wang, Chiao Feng Lin, Otto Valladares, Stacey B. Gabriel, Mark dePristo, David M. Altshuler, Shaun M. Purcell, Matthew W. State, Eric Boerwinkle, Joseph D. Buxbaum, Edwin H. Cook, Richard A. Gibbs, Gerard D. Schellenberg, James S. Sutcliffe, Bernie Devlin, Kathryn Roeder, Mark J. Daly

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	235-242
Number of pages	7
Journal	Neuron
Volume	77
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2012.12.029
Publication status	Published - 23 Jan 2013

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Lim, E. T., Raychaudhuri, S., Sanders, S. J., Stevens, C., Sabo, A., MacArthur, D. G., Neale, B. M., Kirby, A., Ruderfer, D. M., Fromer, M., Lek, M., Liu, L., Flannick, J., Ripke, S., Nagaswamy, U., Muzny, D., Reid, J. G., Hawes, A., Newsham, I., ... Daly, M. J. (2013). Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders. Neuron, 77(2), 235-242. https://doi.org/10.1016/j.neuron.2012.12.029

@article{8b873eb48ffd49979a10fafca4abe884,

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.\}",

year = "2013",

month = jan,

day = "23",

doi = "10.1016/j.neuron.2012.12.029",

language = "English",

volume = "77",

pages = "235--242",

journal = "Neuron",

issn = "0896-6273",

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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, D, Reid, JG, Hawes, A, Newsham, I, Wu, Y, Lewis, L, Dinh, H, Gross, S, Wang, LS, Lin, CF, 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 2013, 'Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders', Neuron, vol. 77, no. 2, pp. 235-242. https://doi.org/10.1016/j.neuron.2012.12.029

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AU - Lim, Elaine T.

AU - Raychaudhuri, Soumya

AU - Sanders, Stephan J.

AU - Stevens, Christine

AU - Sabo, Aniko

AU - MacArthur, Daniel G.

AU - Neale, Benjamin M.

AU - Kirby, Andrew

AU - Ruderfer, Douglas M.

AU - Fromer, Menachem

AU - Lek, Monkol

AU - Liu, Li

AU - Flannick, Jason

AU - Ripke, Stephan

AU - Nagaswamy, Uma

AU - Muzny, Donna

AU - Reid, Jeffrey G.

AU - Hawes, Alicia

AU - Newsham, Irene

AU - Wu, Yuanqing

AU - Lewis, Lora

AU - Dinh, Huyen

AU - Gross, Shannon

AU - Wang, Li San

AU - Lin, Chiao Feng

AU - Valladares, Otto

AU - Gabriel, Stacey B.

AU - dePristo, Mark

AU - Altshuler, David M.

AU - Purcell, Shaun M.

AU - State, Matthew W.

AU - Boerwinkle, Eric

AU - Buxbaum, Joseph D.

AU - Cook, Edwin H.

AU - Gibbs, Richard A.

AU - Schellenberg, Gerard D.

AU - Sutcliffe, James S.

AU - Devlin, Bernie

AU - Roeder, Kathryn

AU - Daly, Mark J.

PY - 2013/1/23

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N2 - 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.

AB - 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.

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DO - 10.1016/j.neuron.2012.12.029

M3 - Article

C2 - 23352160

SN - 0896-6273

VL - 77

SP - 235

EP - 242

JO - Neuron

JF - Neuron

IS - 2

ER -

Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders

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