Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder
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...
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Published in | Science (American Association for the Advancement of Science) Vol. 362; no. 6420 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
The American Association for the Advancement of Science
14.12.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Author contributions: Experimental design, JA, KL, LZ, DMW, HB, NA, JDB, HC, MJD, YSK, GTM, BMN, ARQ, JLR, NS, MWS, AJW, MET, BD, KR, and SJS; Data generation, GBS, JD, CD, YSK, and SJS; Data processing, JA, DMW, SD, CD, MCG, LL, and SJS; Annotation of functional regions, JA, DMW, EM, SP, JLR, NS, and SJS; Data analysis, JA, KL, LZ, DMW, SD, HB, HZW, XZ, GBS, RLC, BBC, LK, MET, BD, KR, and SJS; Statistical analysis, JA, KL, LZ, DMW, LK, MET, BD, KR, and SJS; Manuscript preparation, JA, KL, LZ, DMW, SD, NA, HC, GTM, MET, BD, KR, and SJS. |
ISSN: | 0036-8075 1095-9203 1095-9203 |
DOI: | 10.1126/science.aat6576 |