Article

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

Molecular Autism (Impact Factor: 5.49). 10/2012; 3(1):9. DOI: 10.1186/2040-2392-3-9
Source: PubMed

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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Available from: Arthur Jeremy Willsey, Jul 08, 2015
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    • "Family studies indicate a significant genetic basis for ASD susceptibility, but the underlying genetic architecture is highly complex and heterogeneous. Recent genome-wide studies have documented that common variants exert only small individual main effects on risk, although when common variation (CV) across the genome is considered in aggregate, CV is found to contribute measurably to ASD risk [Klei et al., 2012]. In addition, rare inherited and de novo copy number variants (CNVs) and single nucleotide variants (SNVs) of large effect size have a major role in the etiology of ASD, contributing in as many as 5–10% of idiopathic cases examined [Devlin and Scherer, 2012]. "
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    • "recent exome-sequencing studies identified a highly heterogeneous collection of de novo mutations collectively increasing autism risk by 5-to 20-fold but still incompletely penetrant, meaning that each is not sufficient to cause the disease in most cases (Neale et al., 2012; O'Roak et al., 2011; Persico and Napolioni, 2013). Moreover, common genetic variants collectively account for at least 50% of ASD liability (Klei et al., 2012), although each single variant exerts a small effect (Anney et al., 2012). Thus, ASD is characterized by extreme genetic heterogeneity, with rare and common variants either epistatically causing the disease or conferring variable degrees of vulnerability to potential epigenetic, environmental and immune factors (Persico and Bourgeron, 2006). "
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    • "Large-scale genome-wide association studies have detected common variants in genes such as CDH9, CDH10, NRXN1 and others, which often could not be independently replicated [Autism Genome Project Consortium et al., 2007; Ma et al., 2009; Wang et al., 2009; Curran et al., 2011]. Overall, individual common variants exert weak effects on the risk for ASD [Anney et al., 2012] but by acting additively may explain as much as 60% of the narrow-sense heritability in ASD individuals from multiplex families and approximately 40% for simplex families [Klei et al., 2012]. Thus, assuming a polygenic model, combinations of 2 or more variants may be necessary to cause the full ASD phenotype, as has been found with intellectual delay (ID) [Girirajan et al., 2012]. "
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    ABSTRACT: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
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