Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder
Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder
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DOI：
10.1126/science.aat6576
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发表时间：
2018-12-14
期刊：
影响因子：
56.9
通讯作者：
Sanders, Stephan J.
中科院分区：
文献类型：
--
作者：
An, Joon-Yong;Lin, Kevin;Sanders, Stephan J.
全基因组测序（WGS）促进了首次全基因组评估从头非编码突变对复杂疾病的贡献。使用WGS，我们在来自1902个四重奏家庭的成员的样本基因组中确定了255，106个从头突变，其中一个孩子，而不是兄弟姐妹或他们的父母，受到自闭症谱系障碍（ASD）的影响。与编码突变相反，孤立分析的非编码功能注释类别与ASD显著相关。然而，在多个注释类别的从头风险评分的背景下，铸造非编码变异确实与启动子区域的突变相关。我们发现，这个启动子信号的最强驱动程序来自转录起始位点远端的进化保守的转录因子结合位点。这些数据表明，从头突变的启动子区域，其特征在于进化和功能的签名，有助于ASD。
Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.