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

Joon Yong An, Kevin Lin, Lingxue Zhu, Donna M. Werling, Shan Dong, Harrison Brand, Harold Z. Wang, Xuefang Zhao, Grace B. Schwartz, Ryan L. Collins, Benjamin B. Currall, Claudia Dastmalchi, Jeanselle Dea, Clif Duhn, Michael C. Gilson, Lambertus Klei, Lindsay Liang, Eirene Markenscoff-Papadimitriou, Sirisha Pochareddy, Nadav AhituvJoseph D. Buxbaum, Hilary Coon, Mark J. Daly, Young Shin Kim, Gabor T. Marth, Benjamin M. Neale, Aaron R. Quinlan, John L. Rubenstein, Nenad Sestan, Matthew W. State, A. Jeremy Willsey, Michael E. Talkowski, Bernie Devlin, Kathryn Roeder, Stephan J. Sanders

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


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.

Original languageEnglish
Article number1270
Issue number6420
StatePublished - 14 Dec 2018


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