The contribution of de novo coding mutations to autism spectrum disorder

Ivan Iossifov; Brian J. O'Roak; Stephan J. Sanders; Michael Ronemus; Niklas Krumm; Dan Levy; Holly A. Stessman; Kali T. Witherspoon; Laura Vives; Karynne E. Patterson; Joshua D. Smith; Bryan Paeper; Deborah A. Nickerson; Jeanselle Dea; Shan Dong; Luis E. Gonzalez; Jeffrey D. Mandell; Shrikant M. Mane; Michael T. Murtha; Catherine A. Sullivan; Michael F. Walker; Zainulabedin Waqar; Liping Wei; A. Jeremy Willsey; Boris Yamrom; Yoon Ha Lee; Ewa Grabowska; Ertugrul Dalkic; Zihua Wang; Steven Marks; Peter Andrews; Anthony Leotta; Jude Kendall; Inessa Hakker; Julie Rosenbaum; Beicong Ma; Linda Rodgers; Jennifer Troge; Giuseppe Narzisi; Seungtai Yoon; Michael C. Schatz; Kenny Ye; W. Richard McCombie; Jay Shendure; Evan E. Eichler; Matthew W. State; Michael Wigler

doi:10.1038/nature13908

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The contribution of de novo coding mutations to autism spectrum disorder

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The contribution of de novo coding mutations to autism spectrum disorder

Ivan Iossifov, Brian J. O'Roak, Stephan J. Sanders, Michael Ronemus, Niklas Krumm, Dan Levy, Holly A. Stessman, Kali T. Witherspoon, Laura Vives, Karynne E. Patterson, …

Nature, Vol.515(7526), pp.216-221

515

11/13/2014

DOI: https://doi.org/10.1038/nature13908

PMCID: PMC4313871

PMID: 25363768

Abstract

General

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

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Title: The contribution of de novo coding mutations to autism spectrum disorder
Creators: Ivan Iossifov (Author) - Cold Spring Harbor Laboratory
Brian J. O'Roak (Author) - University of Washington;Oregon Health and Science University
Stephan J. Sanders (Author) - University of California at San Francisco;Yale University
Michael Ronemus (Author) - Cold Spring Harbor Laboratory
Niklas Krumm (Author) - University of Washington
Dan Levy (Author) - Cold Spring Harbor Laboratory
Holly A. Stessman (Author) - University of Washington
Kali T. Witherspoon (Author) - University of Washington
Laura Vives (Author) - University of Washington
Karynne E. Patterson (Author) - University of Washington
Joshua D. Smith (Author) - University of Washington
Bryan Paeper (Author) - University of Washington
Deborah A. Nickerson (Author) - University of Washington
Jeanselle Dea (Author) - University of California at San Francisco
Shan Dong (Author) - Yale University;Peking University
Luis E. Gonzalez (Author) - Yale University
Jeffrey D. Mandell (Author) - University of California at San Francisco
Shrikant M. Mane (Author) - Yale University
Michael T. Murtha (Author) - Yale University
Catherine A. Sullivan (Author) - Yale University
Michael F. Walker (Author) - University of California at San Francisco
Zainulabedin Waqar (Author) - Yale University
Liping Wei (Author) - Peking University;National Institute of Biological Sciences, Beijing
A. Jeremy Willsey (Author) - University of California at San Francisco;Yale University
Boris Yamrom (Author) - Cold Spring Harbor Laboratory
Yoon Ha Lee (Author) - Cold Spring Harbor Laboratory
Ewa Grabowska (Author) - Cold Spring Harbor Laboratory;New York Genome Center
Ertugrul Dalkic (Author) - Cold Spring Harbor Laboratory;Zonguldak Bülent Ecevit University
Zihua Wang (Author) - Cold Spring Harbor Laboratory
Steven Marks (Author) - Cold Spring Harbor Laboratory
Peter Andrews (Author) - Cold Spring Harbor Laboratory
Anthony Leotta (Author) - Cold Spring Harbor Laboratory
Jude Kendall (Author) - Cold Spring Harbor Laboratory
Inessa Hakker (Author) - Cold Spring Harbor Laboratory
Julie Rosenbaum (Author) - Cold Spring Harbor Laboratory
Beicong Ma (Author) - Cold Spring Harbor Laboratory
Linda Rodgers (Author) - Cold Spring Harbor Laboratory
Jennifer Troge (Author) - Cold Spring Harbor Laboratory
Giuseppe Narzisi (Author) - Cold Spring Harbor Laboratory;New York Genome Center
Seungtai Yoon (Author) - Cold Spring Harbor Laboratory
Michael C. Schatz (Author) - Cold Spring Harbor Laboratory
Kenny Ye (Author) - Yeshiva University
W. Richard McCombie (Author) - Cold Spring Harbor Laboratory
Jay Shendure (Author) - University of Washington
Evan E. Eichler (Author) - University of Washington;Howard Hughes Medical Institute
Matthew W. State (Author) - University of California at San Francisco;Yale University
Michael Wigler (Author) - Cold Spring Harbor Laboratory
Publication Details: Nature, Vol.515(7526), pp.216-221
Series: 515
Number of pages: 6
Grant note: Acknowledgements Simons Foundation Autism Research Initiative grants to E.E.E. (SF191889), M.W.S. (M144095 R11154) and M.W. (SF235988) supported this work. Additional support was provided by the Howard Hughes Medical Institute (International Student Research Fellowship to S.J.S.) and the Canadian Institutes of Health Research(Doctoral Foreign StudyAward to A.J.W.).E.E.E. isan Investigator of the Howard Hughes Medical Institute. We thank all the families at the participating SSC sites, as well as the 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 sites for the recruitment and comprehensive assessment of simplex families; the SFARI staff for facilitating access to the SSC; and the Rutgers University Cell andDNA Repository(RUCDR) for accessingbiomaterials. We would also like to thank the CSHL Woodbury Sequencing Center, the Genome Institute at the Washington University School of Medicine, and Yale Center for Genomic Analysis (in particular J. Overton) for generating sequencing data; E. Antoniou and E. Ghiban for their assistance in data production at CSHL; and T. Brooks-Boone, N. Wright-Davis and M. Wojciechowski for their help in administering the project at Yale. The NHLBI GO Exome Sequencing Project and its ongoing studies produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).
Identifiers: 991005928637002656
Academic Unit: Creighton University
Language: English
Resource Type: Journal article

The contribution of de novo coding mutations to autism spectrum disorder

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