Krumm Niklas, Turner Tychele N, Baker Carl, Vives Laura, Mohajeri Kiana, Witherspoon Kali, Raja Archana, Coe Bradley P, Stessman Holly A, He Zong-Xiao, Leal Suzanne M, Bernier Raphael, Eichler Evan E
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.
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 × 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, RIMS1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.
为了评估遗传变异和新生变异对自闭症风险的相对影响，我们从2377个自闭症家庭中生成了一套全面的外显子单核苷酸变异（SNV）和拷贝数变异（CNV）。我们发现，与未受影响的兄弟姐妹相比，保守基因中的私人遗传截短SNV在先证者中富集（优势比=1.14，P=0.0002），这种效应涉及显著的母系向儿子的传递偏差。我们还观察到遗传CNV的偏差，特别是对于小的（<100 kb）、母系遗传的事件（P=0.01），这些事件在CHD8靶基因中富集（P=7.4×10^(-3)）。使用逻辑回归模型，我们表明私人截短SNV和罕见的遗传CNV是自闭症的统计学独立风险因素，优势比分别为1.11（P=0.0002）和1.23（P=0.01）。该分析确定了第二类候选基因（例如，RIMS1、CUL7和LZTR1），其中传递的突变可能会产生一个敏感背景，但不太可能完全显性。
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