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

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• 作者：Elaine T. Lim¹ ; ⁴ ; ⁵ ; ⁶ ; ⁷ ; Soumya Raychaudhuri⁴ ; ⁶ ; ⁹ ; Stephan J. Sanders¹⁰ ; Christine Stevens⁴ ; Aniko Sabo¹¹ ; Daniel G. MacArthur¹ ; ⁴ ; ⁶ ; Benjamin M. Neale¹ ; ⁴ ; ⁵ ; ⁶ ; Andrew Kirby¹ ; ⁴ ; ⁶ ; Douglas M. Ruderfer¹ ; ³ ; ⁴ ; ⁵ ; ⁶ ; ⁸ ; ¹² ; ¹⁴ ; ¹⁵ ; Menachem Fromer¹ ; ³ ; ⁴ ; ⁵ ; ⁶ ; ⁸ ; ¹² ; ¹⁴ ; ¹⁵ ; Monkol Lek¹ ; ⁴ ; ⁶ ; Li Liu¹⁸ ; Jason Flannick¹ ; ² ; ⁴ ; ⁶ ; Stephan Ripke¹ ; ⁴ ; ⁵ ; Uma Nagaswamy¹¹ ; Donna Muzny¹¹ ; Jeffrey G. Reid¹¹ ; Alicia Hawes¹¹ ; Irene Newsham¹¹ ; Yuanqing Wu¹¹ ; Lora Lewis¹¹ ; Huyen Dinh¹¹ ; Shannon Gross¹¹ ; Li-San Wang¹⁹ ; Chiao-Feng Lin¹⁹ ; Otto Valladares¹⁹ ; Stacey B. Gabriel⁴ ; Mark dePristo⁴ ; David M. Altshuler¹ ; ² ; ⁴ ; ⁶ ; Shaun M. Purcell¹ ; ³ ; ⁴ ; ⁵ ; ⁶ ; ⁸ ; ¹² ; ¹⁴ ; ¹⁵ ; NHLBI Exome Sequencing Project
• 刊名：Neuron
• 出版年：2013
• 出版时间：23 January, 2013
• 年：2013
• 卷：77
• 期：2
• 页码：235-242
• 全文大小：302 K

文摘

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Summary

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 (¡Ü5 % 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.