@article{d76e7916c5a848e5a48e289abf070a36,
title = "An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder",
abstract = "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.",
author = "Werling, {Donna M.} and Harrison Brand and An, {Joon Yong} and Stone, {Matthew R.} and Lingxue Zhu and Glessner, {Joseph T.} and Collins, {Ryan L.} and Shan Dong and Layer, {Ryan M.} and Eirene Markenscoff-Papadimitriou and Andrew Farrell and Schwartz, {Grace B.} and Wang, {Harold Z.} and Currall, {Benjamin B.} and Xuefang Zhao and Jeanselle Dea and Clif Duhn and Erdman, {Carolyn A.} and Gilson, {Michael C.} and Rachita Yadav and Handsaker, {Robert E.} and Seva Kashin and Lambertus Klei and Mandell, {Jeffrey D.} and Nowakowski, {Tomasz J.} and Yuwen Liu and Sirisha Pochareddy and Louw Smith and Walker, {Michael F.} and Waterman, {Matthew J.} and Xin He and Kriegstein, {Arnold R.} and Rubenstein, {John L.} and Nenad Sestan and McCarroll, {Steven A.} and Neale, {Benjamin M.} and Hilary Coon and Willsey, {A. Jeremy} and Buxbaum, {Joseph D.} and Daly, {Mark J.} and State, {Matthew W.} and Quinlan, {Aaron R.} and Marth, {Gabor T.} and Kathryn Roeder and Bernie Devlin and Talkowski, {Michael E.} and Sanders, {Stephan J.}",
note = "Funding Information: We are grateful to the families participating in the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection (SSC). This work was supported by grants from the Simons Foundation for Autism Research Initiative (SFARI 385110 to N.S., A.J.W., M.W.S., S.J.S.; 385027 to M.E.T., J.D.B., B.D., M.J.D., X.H., K.R.; 388196 to G.M., H.C., A.R.Q.; and 346042 to M.E.T.), the US National Institutes of Health (R37MH057881 and U01MH111658 to B.D. and K.R.; HD081256 and GM061354 to M.E.T.; U01MH105575 to M.W.S.; U01MH111662 to M.W.S. and S.J.S.; R01MH110928 and U01MH100239-03S1 to M.W.S., S.J.S., A.J.W.; U01MH111661 to J.D.B.; K99DE026824 to H.B.; U01MH100229 to M.J.D.), the Autism Science Foundation to D.M.W., and the March of Dimes to M.E.T. M.E.T. was also supported by the Desmond and Ann Heathwood MGH Research Scholars award. We thank the SSC principal investigators (A. L. Beaudet, R. Bernier, J. Constantino, E. H. Cook Jr, E. Fombonne, D. Geschwind, D. E. Grice, A. Klin, D. H. Ledbetter, C. Lord, C. L. Martin, D. M. Martin, R. Maxim, J. Miles, O. Ousley, B. Peterson, J. Piggot, C. Saulnier, M. W. State, W. Stone, J. S. Sutcliffe, C. A. Walsh, and E. Wijsman) and the coordinators and staff at the SSC clinical sites; the SFARI staff, in particular N. Volfovsky; D. B. Goldstein for contributing to the experimental design; the Rutgers University Cell and DNA repository for accessing biomaterials; and the New York Genome Center for generating the WGS data. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = may,
day = "1",
doi = "10.1038/s41588-018-0107-y",
language = "English",
volume = "50",
pages = "727--736",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "5",
}