title: Most genetic risk for autism resides with common variation.
abstract: A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Trent
authors.initials: T
authors.lastname: Gaugler
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.affiliation: 1] Department of Psychiatry, University of California, San Francisco, San Francisco, California, 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: Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Corneliu A
authors.initials: CA
authors.lastname: Bodea
authors.affiliation: 1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Goldberg
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Ann B
authors.initials: AB
authors.lastname: Lee
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Milind
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Manaa
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
authors.affiliation: 1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reichert
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ripke
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven
authors.identifier: 0000000169944884
authors.initials: S
authors.lastname: Sandin
authors.affiliation: 1] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Icahn Institute for Genomics and Multiscale Biology, 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] Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [5] Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Oscar
authors.initials: O
authors.lastname: Svantesson
authors.affiliation: 1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Abraham
authors.initials: A
authors.lastname: Reichenberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, 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] Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: 1] Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, 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] Friedman Brain Institute, 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] The 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
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013548:Sweden; D055815:Young Adult