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Nat Genet. 2014 Aug;46(8):881-5. doi: 10.1038/ng.3039. Epub 2014 Jul 20.

Most genetic risk for autism resides with common variation.

Author information

1
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
2
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
3
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.
4
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.
5
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
6
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
7
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.
8
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
9
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.
10
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.
11
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.
12
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.

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.

PMID:
25038753
PMCID:
PMC4137411
DOI:
10.1038/ng.3039
[Indexed for MEDLINE]
Free PMC Article

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