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

被引：200

作者：

Lim, Elaine T. ^{[1
,4
,5
,6
,7
,8
]}

Raychaudhuri, Soumya ^{[4
,6
,7
,10
]}

Sanders, Stephan J. ^{[11
,12
]}

Stevens, Christine ^{[4
]}

Sabo, Aniko ^{[13
]}

MacArthur, Daniel G. ^{[1
,4
,6
,7
]}

Neale, Benjamin M. ^{[1
,4
,5
,6
,7
]}

Kirby, Andrew ^{[1
,4
,6
,7
]}

Ruderfer, Douglas M. ^{[1
,3
,4
,5
,6
,7
,9
,14
,16
,17
]}

Fromer, Menachem ^{[1
,3
,4
,5
,6
,7
,9
,14
,16
,17
]}

Lek, Monkol ^{[1
,4
,6
,7
]}

Liu, Li ^{[20
,21
]}

Flannick, Jason ^{[1
,2
,4
,6
,7
]}

Ripke, Stephan ^{[1
,4
,5
]}

Nagaswamy, Uma ^{[13
]}

Muzny, Donna ^{[13
]}

Reid, Jeffrey G. ^{[13
]}

Hawes, Alicia ^{[13
]}

Newsham, Irene ^{[13
]}

Wu, Yuanqing ^{[13
]}

Lewis, Lora ^{[13
]}

Dinh, Huyen ^{[13
]}

Gross, Shannon ^{[13
]}

Wang, Li-San ^{[22
]}

Lin, Chiao-Feng ^{[22
]}

Valladares, Otto ^{[22
]}

Gabriel, Stacey B. ^{[4
]}

dePristo, Mark ^{[4
]}

Altshuler, David M. ^{[1
,2
,4
,6
,7
]}

Purcell, Shaun M. ^{[1
,3
,4
,5
,6
,7
,9
,14
,16
,17
]}

State, Matthew W. ^{[11
,12
]}

Boerwinkle, Eric ^{[13
,24
]}

Buxbaum, Joseph D. ^{[15
,16
,17
,18
,19
]}

Cook, Edwin H. ^{[25
]}

Gibbs, Richard A. ^{[13
]}

Schellenberg, Gerard D. ^{[23
]}

Sutcliffe, James S. ^{[26
,27
]}

Devlin, Bernie ^{[28
]}

Roeder, Kathryn ^{[20
,21
]}

Daly, Mark J. ^{[1
,4
,5
,6
,7
]}

机构：

[1] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA

[4] Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[6] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Harvard Univ, Sch Med, Program Genet & Genom Biol & Biomed Sci, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA

[10] Brigham & Womens Hosp, Div Immunol Allergy & Rheumatol, Boston, MA 02115 USA

[11] Yale Univ, Dept Psychiat, Sch Med, New Haven, CT 06520 USA

[12] Yale Univ, Dept Genet, Sch Med, New Haven, CT 06520 USA

[13] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[14] Mt Sinai Sch Med, Div Psychiat Genom, New York, NY 10029 USA

[15] Mt Sinai Sch Med, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[16] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA

[17] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

[18] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA

[19] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA

[20] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[21] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA

[22] Univ Penn, Penn Ctr Bioinformat, Philadelphia, PA 19104 USA

[23] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[24] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[25] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA

[26] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[27] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Psychiat, Nashville, TN 37232 USA

[28] Univ Pittsburgh, Dept Psychiat, Sch Med, Pittsburgh, PA 15260 USA

来源：

NEURON | 2013年 / 77卷 / 02期

关键词：

COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; CANDIDATE GENES; GENOME; EXOME; VARIANTS; ASSOCIATION; FAMILIES; TOOL;

D O I：

10.1016/j.neuron.2012.12.029

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：235 / 242

页数：8

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