Abstract
BackgroundAutism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. However, novel methods to identify moderate risk alleles in attainable sample sizes are now gaining momentum.MethodsIn this study, we utilized publically available genome-wide association study data from the Autism Genome Project and annotated the results (P <0.001) for expression quantitative trait loci present in the parietal lobe (GSE35977), cerebellum (GSE35974) and lymphoblastoid cell lines (GSE7761). We then performed a test of enrichment by comparing these results to simulated data conditioned on minor allele frequency to generate an empirical P-value indicating statistically significant enrichment of expression quantitative trait loci in top results from the autism genome-wide association study.ResultsOur findings show a global enrichment of brain expression quantitative trait loci, but not lymphoblastoid cell line expression quantitative trait loci, among top single nucleotide polymorphisms from an autism genome-wide association study. Additionally, the data implicates individual genes SLC25A12, PANX1 and PANX2 as well as pathways previously implicated in autism.ConclusionsThese findings provide supportive rationale for the use of annotation-based approaches to genome-wide association studies.
Highlights
Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity
Our study identified significant enrichment of parietal and cerebellum expression quantitative trait loci (eQTL), but not lymphoblastoid cell line (LCL) eQTL, among the top single nucleotide polymorphism (SNP) associations in all four of the primary Autism Genome Project (AGP) genome-wide association studies (GWAS) identified by Anney et al This pattern of results showing significant enrichment in brain and not in tissues peripheral to the main pathology was seen in a study of cis-regulatory SNPs in bipolar disorder [13]
We found that the risk alleles of the SLC25A12 eQTL SNPs identified in the AGP GWAS are correlated with decreased expression of SLC25A12 in the parietal lobe
Summary
Autism spectrum disorder is a severe early onset neurodevelopmental disorder with high heritability but significant heterogeneity. Traditional genome-wide approaches to test for an association of common variants with autism susceptibility risk have met with limited success. The study of autism genetics began with twin studies conducted as early as the 1970s [2], indicating a strong heritable component. The discovery of genetic variants involved in autism has been confounded by phenotypic, genetic and allelic heterogeneity, multiple modes of transmission, inconsistent application of diagnostic criteria and unknown environmental risks. Progress has been made in our understanding of the genetic architecture of autism despite these complexities. Few genes harboring common risk factors have been convincingly implicated in the etiology of autism
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