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

Klei, L and Sanders, SJ and Murtha, MT and Hus, V and Lowe, JK and Willsey, AJ and Moreno-De-Luca, D and Yu, TW and Fombonne, E and Geschwind, D and Grice, DE and Ledbetter, DH and Lord, C and Mane, SM and Martin, CL and Martin, DM and Morrow, EM and Walsh, CA and Melhem, NM and Chaste, P and Sutcliffe, JS and State, MW and Cook, EH and Roeder, K and Devlin, B (2012) Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism, 3 (1).

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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. © 2012 Klei et al.; licensee BioMed Central Ltd.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Klei, L Sanders, SJ Murtha, MT Hus, V Lowe, JK Willsey, AJ Moreno-De-Luca, D Yu, TW Fombonne, E Geschwind, D Grice, DE Ledbetter, DH Lord, C Mane, SM Martin, CL Martin, DM Morrow, EM Walsh, CA Melhem, NM nam19@pitt.edu NAM19 0000-0001-8572-8487 Chaste, P Sutcliffe, JS State, MW Cook, EH Roeder, K Devlin, B devlinbj@pitt.edu DEVLINBJ
Date:	1 December 2012
Date Type:	Publication
Journal or Publication Title:	Molecular Autism
Volume:	3
Number:	1
DOI or Unique Handle:	10.1186/2040-2392-3-9
Schools and Programs:	School of Medicine > Psychiatry
Refereed:	Yes
Date Deposited:	30 Nov 2016 17:21
Last Modified:	01 Oct 2019 15:00
URI:	http://d-scholarship.pitt.edu/id/eprint/29813

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