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PMID: 29700473 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 50 ·No. 5 ·2018-00-26 ·Pages 727-736

Werling DM, Brand H, An JY, 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, Willsey AJ, Buxbaum JD, Daly MJ, State MW, Quinlan AR, Marth GT, Roeder K, Devlin B, Talkowski ME, Sanders SJ

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.

MeSH Terms
Autism Spectrum Disorder/genetics Female Genetic Predisposition to Disease/genetics Genome/genetics Genome-Wide Association Study/methods Humans INDEL Mutation/genetics Male Polymorphism, Single Nucleotide/genetics Protein Isoforms/genetics
Chemicals
Protein Isoforms
Authors & Affiliations
47 authors, click to expand affiliations / ORCID
Werling Donna M ORCID
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Brand Harrison
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
An Joon-Yong ORCID
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Stone Matthew R
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Zhu Lingxue
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA.
Glessner Joseph T
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Collins Ryan L ORCID
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Bioinformatics and Integrative Genomics, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
Dong Shan
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Layer Ryan M ORCID
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. | USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA.
Markenscoff-Papadimitriou Eirene
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Farrell Andrew
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. | USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA.
Schwartz Grace B
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Wang Harold Z
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Currall Benjamin B
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Zhao Xuefang
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Dea Jeanselle
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Duhn Clif
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Erdman Carolyn A
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Gilson Michael C
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Yadav Rachita
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. | Department of Neurology, Harvard Medical School, Boston, MA, USA. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Handsaker Robert E ORCID
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. | Department of Genetics, Harvard Medical School, Boston, MA, USA.
Kashin Seva
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. | Department of Genetics, Harvard Medical School, Boston, MA, USA.
Klei Lambertus
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Mandell Jeffrey D
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Nowakowski Tomasz J
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. | Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. | Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
Liu Yuwen
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Pochareddy Sirisha
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Smith Louw
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Walker Michael F
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Waterman Matthew J
Department of Biology, Eastern Nazarene College, Quincy, MA, USA.
He Xin ORCID
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Kriegstein Arnold R
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
Rubenstein John L
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Sestan Nenad ORCID
Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
McCarroll Steven A
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. | Department of Genetics, Harvard Medical School, Boston, MA, USA.
Neale Benjamin M ORCID
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. | Analytical and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. | Department of Medicine, Harvard Medical School, Boston, MA, USA.
Coon Hilary
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT, USA. | Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Willsey A Jeremy
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. | Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Buxbaum Joseph D
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Daly Mark J ORCID
Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. | Analytical and Translational Genetics Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. | Department of Medicine, Harvard Medical School, Boston, MA, USA.
State Matthew W
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Quinlan Aaron R ORCID
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. | USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA. | Department of Biomedical Informatics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Marth Gabor T ORCID
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA. | USTAR Center for Genetic Discovery, University of Utah School of Medicine, Salt Lake City, UT, USA.
Roeder Kathryn
Department of Statistics, Carnegie Mellon University, Pittsburgh, PA, USA. | Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA.
Devlin Bernie
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. [email protected].
Talkowski Michael E ORCID
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital, Boston, MA, USA. [email protected]. | Department of Neurology, Harvard Medical School, Boston, MA, USA. [email protected]. | Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA. [email protected]. | Departments of Pathology and Psychiatry, Massachusetts General Hospital, Boston, MA, USA. [email protected].
Sanders Stephan J
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. [email protected].
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/s41588-018-0107-y
Email
[email protected]
[email protected]
[email protected]
Published
2018-00-26
Epub
2018-00-26
Pages
727-736
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC5961723
Subset
IM
Grants
NIMH NIH HHS · R01 MH110928 · United States
NIMH NIH HHS · R37 MH057881 · United States
NIMH NIH HHS · U01 MH105575 · United States
NIMH NIH HHS · U01 MH100229 · United States
NIDCR NIH HHS · K99 DE026824 · United States
NIMH NIH HHS · U01 MH111660 · United States
NIMH NIH HHS · U01 MH100239 · United States
NINDS NIH HHS · R35 NS097305 · United States
NIMH NIH HHS · U01 MH111658 · United States
NIMH NIH HHS · U01 MH111661 · United States
NIGMS NIH HHS · P01 GM061354 · United States
NIMH NIH HHS · R01 MH109901 · United States
NICHD NIH HHS · R01 HD081256 · United States
NIMH NIH HHS · U01 MH111662 · United States
NIMH NIH HHS · R01 MH109904 · United States
NIMH NIH HHS · R01 MH109900 · United States
Corrections
CommentIn
PMID: 29700466
CommentIn
PMID: 29700468
External Links
PubMed source DOI: 10.1038/s41588-018-0107-y PMC Full Text View journal details
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