Most genetic risk for autism resides with common variation. J. D. Buxbaum1, B. Devlin2, K. Roeder3, and the Population-based Autism Genetics and Environment Study (PAGES) Consortium 1) Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY; 2) Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA; 3) Statistics, Carnegie Mellon University, Pittsburgh, PA.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder typified by striking deficits in social communication. A key component of genetic architecture is the allelic spectrum influencing trait variability. For idiopathic ASD, the nature of its allelic spectrum is uncertain. Individual risk genes have been identified from rare variation, especially de novo mutations. From this evidence one might conclude that rare variation dominates its allelic spectrum, 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. Using a unique epidemiological sample from Sweden, novel methods that distinguish total narrow-sense heritability from that due to common variation, and by synthesizing results from other studies, we reach several conclusions about ASD genetic architecture: its narrow-sense heritability is 54% and most traces to common variation; rare de novo mutations contribute substantially to individuals liability; still their contribution to variance in liability, 2.6%, is modest compared to heritable variation. Concurrent with our study, a comprehensive family study of autism in Sweden has been ongoing and it recently reported the largest study of familial risk for autism to date. The study analyzed additive and non-additive genetic effects and shared and non-shared environmental effects in a series of structured models to estimate which factors have a substantial effect on RR and thus heritability. The best model, consisting only of additive genetic and non-shared environmental effects, yielded quite precise estimates of the narrow-sense heritability of AD (h2=54%, SE=5). That these studies, with very different design, converge on similar estimates of heritability lends strong support for our conclusion that the bulk of risk for autism arises from genetic variation. This study was supported by National Institute of Mental Health (NIMH) Grants MH057881 and MH097849.
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