Abstract
BackgroundRestricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors. Previous research indicates that there are two or more factors (subcategories) within the RRB domain. In an effort to identify common variants associated with RRB, we have carried out a genome-wide association study (GWAS) using the Autism Genetic Resource Exchange (AGRE) dataset (n = 1,335, all ASD probands of European ancestry) for each identified RRB subcategory, while allowing for comparisons of associated single nucleotide polymorphisms (SNPs) with associated SNPs in the same set of probands analyzed using all the RRB subcategories as phenotypes in a multivariate linear mixed model. The top ranked SNPs were then explored in an independent dataset.ResultsUsing principal component analysis of item scores obtained from Autism Diagnostic Interview-Revised (ADI-R), two distinct subcategories within Restricted and Repetitive Behaviors were identified: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS). Quantitative RSM and IS scores were subsequently used as phenotypes in a GWAS using the AGRE ASD cohort. Although no associated SNPs with genome-wide significance (P < 5.0E-08) were detected when RSM or IS were analyzed independently, three SNPs approached genome-wide significance when RSM and IS were considered together using multivariate association analysis. These included the top IS-associated SNP, rs62503729 (P-value = 6.48E-08), which is located within chromosome 8p21.2-8p21.1, a locus previously linked to schizophrenia. Notably, all of the most significantly associated SNPs are located in close proximity to STMN4 and PTK2B, genes previously shown to function in neuron development. In addition, several of the top-ranked SNPs showed correlations with STMN4 mRNA expression in adult CEU (Caucasian and European descent) human prefrontal cortex. However, the association signals within chromosome 8p21.2-8p21.1 failed to replicate in an independent sample of 2,588 ASD probands; the insufficient sample size and between-study heterogeneity are possible explanations for the non-replication.ConclusionsOur analysis indicates that RRB in ASD can be represented by two distinct subcategories: RSM and IS. Subsequent univariate and multivariate genome-wide association studies of these RRB subcategories enabled the detection of associated SNPs at 8p21.2-8p21.1. Although these results did not replicate in an independent ASD dataset, genomic features of this region and pathway analysis suggest that common variants in 8p21.2-8p21.1 may contribute to RRB, particularly IS. Together, these observations warrant future studies to elucidate the possible contributions of common variants in 8p21.2-8p21.1 to the etiology of RSM and IS in ASD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2475-y) contains supplementary material, which is available to authorized users.
Highlights
Restricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors
Our analysis indicates that RRB in ASD can be represented by two distinct subcategories: Repetitive Sensory Motor (RSM) and Insistence on Sameness (IS)
Subsequent univariate and multivariate genome-wide association studies of these RRB subcategories enabled the detection of associated single nucleotide polymorphisms (SNPs) at 8p21.2-8p21.1
Summary
Restricted and Repetitive Behaviors (RRB), one of the core symptom categories for Autism Spectrum Disorders (ASD), comprises heterogeneous groups of behaviors. Autism Spectrum Disorder (ASD) is characterized by impaired reciprocal social interactions, delayed or aberrant communication, and the presence of restricted and repetitive behaviors, frequently with restricted interests [1]. These disabilities often confer significant lifelong burdens on individuals with ASD. Genome-wide association studies (GWAS) have implicated the region on chromosome 5p14.1 between CDH9 and CDH10 as the first potential common genetic risk factor for ASD in Caucasian populations [9, 10]. Phenotype and genetic heterogeneity between patients are conjectured to greatly reduce the power of overall genome-wide case-control studies in ASD, and is a likely explanation for the lack of replication and much of the ‘missing heritability’ in this complex disease [15]. One proposed approach to increase statistical power to detect pathogenic loci is to design genetic association studies focusing on ASD sub-phenotypes [16,17,18,19]
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