Excess of rare, inherited truncating mutations in autism

被引：448

作者：

Krumm, Niklas ^{[1
]}

Turner, Tychele N. ^{[1
]}

Baker, Carl ^{[1
]}

Vives, Laura ^{[1
]}

Mohajeri, Kiana ^{[1
]}

Witherspoon, Kali ^{[1
]}

Raja, Archana ^{[1
,2
]}

Coe, Bradley P. ^{[1
]}

Stessman, Holly A. ^{[1
]}

He, Zong-Xiao ^{[3
]}

Leal, Suzanne M. ^{[3
]}

Bernier, Raphael ^{[4
]}

Eichler, Evan E. ^{[1
,2
]}

机构：

[1] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98104 USA

[2] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[3] Baylor Coll Med, Dept Mol & Human Genet, Ctr Stat Genet, Houston, TX 77030 USA

[4] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 06期

基金：

美国国家卫生研究院;

关键词：

DE-NOVO MUTATIONS; TRANSMISSION DISEQUILIBRIUM; GROWTH-FACTOR; GENES; MODEL; DELETIONS; SUPPORTS; CHD8; RISK; CNVS;

D O I：

10.1038/ng.3303

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0.01) that are enriched in CHD8 target genes (P = 7.4 x 10(-3)). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (P = 0.0002) and 1.23 (P = 0.01), respectively. This analysis identifies a second class of candidate genes (for example, RIMS 1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.

引用

页码：582 / 588

页数：7

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