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Nat Genet DOI:10.1038/s41588-018-0107-y

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.

Publication TypeJournal Article
Year of Publication2018
AuthorsWerling, DM, Brand, H, An, J-Y, Stone, MR, Zhu, L, Glessner, JT, Collins, RL, Dong, S, Layer, RM, Markenscoff-Papadimitriou, E, Farrell, A, Schwartz, GB, Wang, HZ, Currall, BB, Zhao, X, Dea, J, Duhn, C, Erdman, CA, Gilson, MC, Yadav, R, Handsaker, RE, Kashin, S, Klei, L, Mandell, JD, Nowakowski, TJ, Liu, Y, Pochareddy, S, Smith, L, Walker, MF, Waterman, MJ, He, X, Kriegstein, AR, Rubenstein, JL, Sestan, N, McCarroll, SA, Neale, BM, Coon, H, A Willsey, J, Buxbaum, JD, Daly, MJ, State, MW, Quinlan, AR, Marth, GT, Roeder, K, Devlin, B, Talkowski, ME, Sanders, SJ
JournalNat Genet
Date Published2018 04 26
KeywordsAutism Spectrum Disorder, Female, Genetic Predisposition to Disease, Genome, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Polymorphism, Single Nucleotide, Protein Isoforms

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.


Alternate JournalNat. Genet.
PubMed ID29700473
PubMed Central IDPMC5961723
Grant ListR01 MH110928 / MH / NIMH NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
U01 MH105575 / MH / NIMH NIH HHS / United States
U01 MH100229 / MH / NIMH NIH HHS / United States
K99 DE026824 / DE / NIDCR NIH HHS / United States
U01 MH111660 / MH / NIMH NIH HHS / United States
U01 MH100239 / MH / NIMH NIH HHS / United States
R35 NS097305 / NS / NINDS NIH HHS / United States
U01 MH111658 / MH / NIMH NIH HHS / United States
U01 MH111661 / MH / NIMH NIH HHS / United States
P01 GM061354 / GM / NIGMS NIH HHS / United States
R01 MH109901 / MH / NIMH NIH HHS / United States
R01 HD081256 / HD / NICHD NIH HHS / United States
U01 MH111662 / MH / NIMH NIH HHS / United States
R01 MH109900 / MH / NIMH NIH HHS / United States