title: A framework for the interpretation of de novo mutation in human disease.
abstract: Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [4] Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Elise B
authors.initials: EB
authors.lastname: Robinson
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: 1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Stevens
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Aniko
authors.initials: A
authors.lastname: Sabo
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: McGrath
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kosmicki
authors.affiliation: 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [2] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Swapan
authors.initials: S
authors.lastname: Mallick
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kirby
authors.affiliation: 1] Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Wall
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Synapdx, Lexington, Massachusetts, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: DePristo
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [4] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Purcell
authors.affiliation: 1] Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [3] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: 1] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA. [2] Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 1] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [4] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [6] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.affiliation: 1] Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA. [2] Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.affiliation: 1] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D059472:Exome; D005260:Female; D005815:Genetic Code; D020022:Genetic Predisposition to Disease; D005826:Genetics, Medical / Q000379:methods; D006801:Humans; D008297:Male; D009154:Mutation
references.citation: Nature. 2012 Apr 04;485(7397):242-5
references.pmid: 22495311
references.citation: Nature. 1991 Jun 20;351(6328):652-4
references.pmid: 1904993
references.citation: Genome Res. 2010 Sep;20(9):1297-303
references.pmid: 20644199
references.citation: Nat Genet. 2011 May;43(5):491-8
references.pmid: 21478889
references.citation: Nat Genet. 2011 Jun;43(6):585-9
references.pmid: 21572417
references.citation: Am J Hum Genet. 2012 Dec 7;91(6):1033-40
references.pmid: 23176822
references.citation: Cell. 2011 Jul 22;146(2):247-61
references.pmid: 21784246
references.citation: Neuron. 2012 Apr 26;74(2):285-99
references.pmid: 22542183
references.citation: Nature. 2012 Apr 04;485(7397):246-50
references.pmid: 22495309
references.citation: Nature. 2013 Sep 12;501(7466):217-21
references.pmid: 23934111
references.citation: Nat Genet. 2011 Jun 12;43(7):712-4
references.pmid: 21666693
references.citation: Neuron. 2011 Jun 9;70(5):863-85
references.pmid: 21658581
references.citation: Bioinformatics. 2010 Mar 1;26(5):589-95
references.pmid: 20080505
references.citation: PLoS Genet. 2013;9(8):e1003709
references.pmid: 23990802
references.citation: Nat Genet. 2012 Dec;44(12):1365-9
references.pmid: 23042115
references.citation: Nature. 2005 Oct 20;437(7062):1153-7
references.pmid: 16237444
references.citation: N Engl J Med. 2012 Nov 15;367(20):1921-9
references.pmid: 23033978
references.citation: Am J Hum Genet. 2007 Apr;80(4):727-39
references.pmid: 17357078
references.citation: Science. 2012 Dec 21;338(6114):1619-22
references.pmid: 23160955
references.citation: Brain Res. 2011 Mar 22;1380:42-77
references.pmid: 21129364
references.citation: Nat Genet. 2010 Sep;42(9):790-3
references.pmid: 20711175
references.citation: Nat Genet. 2012 Nov;44(11):1277-81
references.pmid: 23001126
references.citation: Nature. 2012 Apr 04;485(7397):237-41
references.pmid: 22495306
references.citation: Lancet. 2012 Nov 10;380(9854):1674-82
references.pmid: 23020937