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.

Gaugler T¹, Klei L², Sanders SJ³, Bodea CA¹, Goldberg AP⁴, Lee AB¹, Mahajan M⁵, Manaa D⁵, Pawitan Y⁶, Reichert J⁷, Ripke S⁸, Sandin S⁶, Sklar P⁹, Svantesson O⁶, Reichenberg A¹⁰, Hultman CM⁶, Devlin B², Roeder K¹¹, Buxbaum JD¹².

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.

Comment in

Common genetic variants linked with large percentage of autism risk: study finds spontaneous mutations are less-significant risk factors. [Am J Med Genet A. 2014]
Autism genes: the continuum that connects us all. [J Genet. 2016]

PMID:: 25038753
PMCID:: PMC4137411
DOI:: 10.1038/ng.3039

[Indexed for MEDLINE]

Free PMC Article

Images from this publication.See all images (2)Free text

Figure 1

Results for PAGES (Population-based Autism Genetics and Environment Study), the Swedish study of the heritability of autism. (a) Heritability estimate (95% confidence interval) compared across study designs and analytical methods. Horizontal reference is the PAGES estimate of heritability from SNP genotypes. Twin studies: 1 California twins for strict autism (95% confidence interval: 8–84%), the largest twin study to date using diagnosis only; 2, Swedish twins 9–12 years old (95% confidence interval: 29–91%); 3, Swedish twins 9–12 years old characterized for a quantitative measure of autism (most extreme cutoff; 95% confidence interval: 44–74%). SNP-based estimates of heritability: 4, Swedish family study (95% confidence interval: 44–64%); 5, simplex cases versus population controls (95% confidence interval: 26–73%); 6, multiplex autism cases versus population controls (95% confidence interval: 38–93%). SNP-based estimates from the PAGES study, assuming prevalence K=0.3%; 7, heritability due to common variants using autism cases versus population controls (95% confidence interval: 31–69%); 8, total narrow-sense heritability due to both common and rare variation using smoothed estimates of relatedness (95% confidence interval: 35–71%). (b) Heritability per chromosome versus length in cM. (c) Prevalence by county for all 21 counties in Sweden tallied by birth year cohort. Each boxplot has a lower tail that extends from the minimum county-level prevalence to the 25^th percentile; a central box that begins at the 25^th percentile and ends at the 75^th percentile, with a line demarcating the median prevalence; and an upper tail that extends from the 75^th percentile to either (1) the maximum county-level prevalence (in the absence of any outliers) or (2) to a value of the 75^th percentile + 1.5 times the vertical distance covered by the box – in this case, any outliers that exceed this end of the tail are noted by circular points on the plot. (d) PAGES heritability versus population prevalence of autism for two estimators of heritability: case-control contrast using SNP genotypes (green); total heritability from smoothed relationships amongst subjects, based on SNP genotypes (blue). Beyond the analysis of the PAGES study we applied meta-analysis of selected h² estimates (Methods) to obtain h² = 51.4% (SE = 5.2), which corresponds to a 95% confidence interval of (41.0, 61.8). Contrasting this with the comprehensive estimate of h² obtained from the Swedish family study (h² = 54%, SE = 5) produces an estimate of h² due to rare variants: h² = 2.6% (SE = 7.2, 95% confidence interval: 0–17%). Hence we conclude that common variants explain the bulk of the heritability for autism, at least 41% of the variability, and rare variants explain at most 17%, based on the upper and lower bounds of the respective 95% confidence intervals.

Most genetic risk for autism resides with common variation

Nat Genet. 2014 Aug;46(8):881-885.