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

• Published in: Science (American Association for the Advancement of Science) Vol. 362; no. 6420
• Main Authors: An, Joon-Yong, Lin, Kevin, Zhu, Lingxue, Werling, Donna M, Dong, Shan, Brand, Harrison, Wang, Harold Z, Zhao, Xuefang, Schwartz, Grace B, Collins, Ryan L, Currall, Benjamin B, Dastmalchi, Claudia, Dea, Jeanselle, Duhn, Clif, Gilson, Michael C, Klei, Lambertus, Liang, Lindsay, Markenscoff-Papadimitriou, Eirene, Pochareddy, Sirisha, Ahituv, Nadav, Buxbaum, Joseph D, Coon, Hilary, Daly, Mark J, Kim, Young Shin, Marth, Gabor T, Neale, Benjamin M, Quinlan, Aaron R, Rubenstein, John L, Sestan, Nenad, State, Matthew W, Willsey, A Jeremy, Talkowski, Michael E, Devlin, Bernie, Roeder, Kathryn, Sanders, Stephan J
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 14.12.2018
• Subjects: Annotations; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorders; Binding sites; Binding Sites - genetics; Categories; Children; Coding; Conserved Sequence; Deoxyribonucleic acid; Disorders; Disruption; DNA; DNA Mutational Analysis; Evolution; Family (Sociological Unit); Gene sequencing; Genes; Genetic diversity; Genetic Loci; Genetic Variation; Genetics; Genomes; Humans; Learning algorithms; Machine learning; Mutation; Neurodevelopmental disorders; Non-coding RNA; Nucleotides; Parents; Pedigree; Promoter Regions, Genetic - genetics; Proteins; Risk; Transcription factors; Transcription Factors - metabolism; Wildlife conservation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aat6576

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.