Genome-wide de novo risk score implicates promotervariation in autism spectrum disorder

摘要

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 assess genetic variation from 7,608 samples in 1,902 autism spectrum disorder (ASD) families, identifying 255,106 de novo mutations. In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, is significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, does demonstrate association with mutations localized to promoter regions. 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.