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 journalArticle

11 Citations (Scopus)

Abstract

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
JournalScience
Volume362
Issue number6420
DOIs
Publication statusPublished - 2018 Dec 14
Externally publishedYes

Fingerprint

Genome
Mutation
Genetic Promoter Regions
Transcription Initiation Site
Siblings
Transcription Factors
Parents
Binding Sites
Autism Spectrum Disorder

ASJC Scopus subject areas

  • General

Cite this

An, J-Y., Lin, K., Zhu, L., Werling, D. M., Dong, S., Brand, H., ... Sanders, S. J. (2018). Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science, 362(6420), [1270]. https://doi.org/10.1126/science.aat6576

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

In: Science, Vol. 362, No. 6420, 1270, 14.12.2018.

Research output: Contribution to journalArticle

An, J-Y, Lin, K, Zhu, L, Werling, DM, Dong, S, Brand, H, Wang, HZ, Zhao, X, Schwartz, GB, Collins, RL, Currall, BB, Dastmalchi, C, Dea, J, Duhn, C, Gilson, MC, Klei, L, Liang, L, Markenscoff-Papadimitriou, E, Pochareddy, S, Ahituv, N, Buxbaum, JD, Coon, H, Daly, MJ, Kim, YS, Marth, GT, Neale, BM, Quinlan, AR, Rubenstein, JL, Sestan, N, State, MW, Willsey, AJ, Talkowski, ME, Devlin, B, Roeder, K & Sanders, SJ 2018, 'Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder', Science, vol. 362, no. 6420, 1270. https://doi.org/10.1126/science.aat6576
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. / Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. In: Science. 2018 ; Vol. 362, No. 6420.
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AU - Wang, Harold Z.

AU - Zhao, Xuefang

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AU - Dastmalchi, Claudia

AU - Dea, Jeanselle

AU - Duhn, Clif

AU - Gilson, Michael C.

AU - Klei, Lambertus

AU - Liang, Lindsay

AU - Markenscoff-Papadimitriou, Eirene

AU - Pochareddy, Sirisha

AU - Ahituv, Nadav

AU - Buxbaum, Joseph D.

AU - Coon, Hilary

AU - Daly, Mark J.

AU - Kim, Young Shin

AU - Marth, Gabor T.

AU - Neale, Benjamin M.

AU - Quinlan, Aaron R.

AU - Rubenstein, John L.

AU - Sestan, Nenad

AU - State, Matthew W.

AU - Willsey, A. Jeremy

AU - Talkowski, Michael E.

AU - Devlin, Bernie

AU - Roeder, Kathryn

AU - Sanders, Stephan J.

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