Common genetic variants, acting additively, are a major source of risk for autism - PubMed (original) (raw)

doi: 10.1186/2040-2392-3-9.

Stephan J Sanders, Michael T Murtha, Vanessa Hus, Jennifer K Lowe, A Jeremy Willsey, Daniel Moreno-De-Luca, Timothy W Yu, Eric Fombonne, Daniel Geschwind, Dorothy E Grice, David H Ledbetter, Catherine Lord, Shrikant M Mane, Christa Lese Martin, Donna M Martin, Eric M Morrow, Christopher A Walsh, Nadine M Melhem, Pauline Chaste, James S Sutcliffe, Matthew W State, Edwin H Cook Jr, Kathryn Roeder, Bernie Devlin

Affiliations

Common genetic variants, acting additively, are a major source of risk for autism

Lambertus Klei et al. Mol Autism. 2012.

Abstract

Background: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals.

Methods: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status.

Results: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating.

Conclusions: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

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Figures

Figure 1

Figure 1

Estimated heritability for Autism Spectrum Disorders from ASD probands (Pr), as well as for their mothers (Mo), fathers (Fa), siblings (Si) and pseudo-controls (Pc). Blue dotted reference line is set to the estimated heritability from probands; the black line marks the expected heritability for first degree relatives; and the gray line marks the expected heritability from pseudo-controls. Expected values derived from simulations mimicking the recruitment strategy producing the samples for (A)-(D). (A) Simons Simplex Collection or SSC data; (B) Autism Genome Project or AGP data; (C) AGP data, only simplex families; (D) AGP data, only multiplex families.

Figure 2

Figure 2

Estimated heritability per chromosome for simplex and muliplex families. In this figure chromosome X is marked distinctly, but each chromosome is mapped by its length.

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