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A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet

Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.
Human Molecular Genetics (Impact Factor: 6.68). 10/2010; 19(20):4072-82. DOI: 10.1093/hmg/ddq307
Source: PubMed

ABSTRACT Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

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    • "Overall, we did not discover any polymorphisms in the mother's genome that reached genome-wide significance. However, it is worth noting that the three largest common variant studies to date on the children themselves also did not replicate each other for any common variants reaching genome-wide significance [Anney et al., 2010; Wang et al., 2009; Weiss, Arking, Daly, & Chakravarti, 2009]. They did, however, identify an excess of independent regions with P < 10E-5 and P < 10E-4, suggesting that there may be a large number of alleles of effective size marginally below their power to detect [Weiss et al., 2009]. "
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    ABSTRACT: Like most psychiatric disorders, autism spectrum disorders have both a genetic and an environmental component. While previous studies have clearly demonstrated the contribution of in utero (prenatal) environment on autism risk, most of them focused on transient environmental factors. Based on a recent sibling study, we hypothesized that environmental factors could also come from the maternal genome, which would result in persistent effects across siblings. In this study, the possibility of maternal genotype effects was examined by looking for common variants (single-nucleotide polymorphisms or SNPs) in the maternal genome associated with increased risk of autism in children. A case/control genome-wide association study was performed using mothers of probands as cases, and either fathers of probands or normal females as controls. Autism Genetic Resource Exchange and Illumina Genotype Control Database were used as our discovery cohort (n = 1616). The same analysis was then replicated on Simon Simplex Collection and Study of Addiction: Genetics and Environment datasets (n = 2732). We did not identify any SNP that reached genome-wide significance (P < 10(-8) ), and thus a common variant of large effect is unlikely. However, there was evidence for the possibility of a large number of alleles of effective size marginally below our power to detect. Autism Res 2014, ●●: ●●-●●. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 04/2014; 7(2). DOI:10.1002/aur.1363 · 4.53 Impact Factor
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    • "The scoring strategy is a powerful alternative to reduce the " noise " variants by excluding SNPs in genes without functional evidence. Moreover, the proportion of genetic variance explained by GWAS data increased when the P-value association threshold for autism was increased from 10 −5 to 0.5, similar to observations in related neurodevelopmental disorders, which suggests that thresholds used in the present GWAS could be relaxed to enrich the GS models with true variants (Purcell et al., 2009; Anney et al., 2010). A pathway-based approach was proposed in autism to prioritize SNPs from GWAS and design a polygenic score that could predict autism diagnosis with good accuracy (Skafidas et al., 2012). "
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    • "A number of groups have been attempting to understand the genetics of ASD [21] and the impact of rare copy number variants [22]. In recent studies, the expression profiles of Blymphocytes from ASD individuals and age-matched controls were analyzed by cDNA microarrays [23] [24]. "
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