Dataset Information

Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders.

ABSTRACT: Restricted 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.Using 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.Our 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.

SUBMITTER: Tao Y

PROVIDER: S-EPMC4774106 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders.

Tao Yu Y Gao Hui H Ackerman Benjamin B Guo Wei W Saffen David D Shugart Yin Yao YY

BMC genomics 20160301

<h4>Background</h4>Restricted 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 ...[more]

PMID: 26931105

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Project description:The current study aimed to explore the factor structure of a broad range of restricted and repetitive behaviors (RRB) within the autism spectrum. Exploratory structural equation modeling was conducted using individual item-level data from the Diagnostic Interview for Social and Communication Disorders (DISCO). DISCO is a comprehensive semi-structured interview used by clinicians to elicit information from caregivers about the individual's profile of development and behavior. Data from a sample of 226 individuals with a clinical diagnosis of autism spectrum disorder (ASD) (189 males; Mage = 11.82 years, SDage = 7.87) were analyzed. The six-factor structure provided the most optimal and interpretable fit (comparative fit index = 0.944, Tucker-Lewis index = 0.923, root mean square error of approximation = 0.018). Derived factors were interpreted as repetitive motor behaviors (RMB), unusual sensory and object focused interests (USOI), sensory sensitivity (SS), insistence on sameness (IS), circumscribed interests (CI) and stereotyped language (SL). Age was significantly negatively associated with RMB, USOI and SL but not with SS, IS or CI factor scores. None of the factors were associated with sex. ASD individuals with intellectual disability (ID) had the highest RMB, USOI, SS and SL scores while those without ID had the highest IS and CI scores. Our findings provide preliminary evidence for the utility of the DISCO as a comprehensive measure of several distinct RRB domains in both research and clinical contexts. Importantly, the current investigation highlights crucial areas for measurement development. LAY SUMMARY: The diagnostic Interview for Social and Communication Disorders (DISCO) is a detailed caregiver report clinical interview designed to capture a wide range of key features associated with autism spectrum disorder, including restricted and repetitive behaviors (RRB). This paper provides initial evidence that the DISCO is a promising measure for assessing a wide range of RRB including repetitive motor behaviors, insistence on sameness, circumscribed interests, unusual interests in sensory stimuli, sensory sensitivity and stereotypic language.

Project description:BackgroundSLC25A12 was previously identified by a linkage-directed association analysis in autism. In this study, we investigated the relationship between three SLC25A12 single nucleotide polymorphisms (SNPs) (rs2056202, rs908670 and rs2292813) and restricted repetitive behavior (RRB) traits in autism spectrum disorders (ASDs), based on a positive correlation between the G allele of rs2056202 and an RRB subdomain score on the Autism Diagnostic Interview-Revised (ADI-R).MethodsWe used the Repetitive Behavior Scale-Revised (RBS-R) as a quantitative RRB measure, and conducted linear regression analyses for individual SNPs and a previously identified haplotype (rs2056202-rs2292813). We examined associations in our University of Illinois at Chicago-University of Florida (UIC-UF) sample (179 unrelated individuals with an ASD), and then attempted to replicate our findings in the Simons Simplex Collection (SSC) sample (720 ASD families).ResultsIn the UIC-UF sample, three RBS-R scores (ritualistic, sameness, sum) had positive associations with the A allele of rs2292813 (p = 0.006-0.012) and with the rs2056202-rs2292813 haplotype (omnibus test, p = 0.025-0.040). The SSC sample had positive associations between the A allele of rs2056202 and four RBS-R scores (stereotyped, sameness, restricted, sum) (p = 0.006-0.010), between the A allele of rs908670 and three RBS-R scores (stereotyped, self-injurious, sum) (p = 0.003-0.015), and between the rs2056202-rs2292813 haplotype and six RBS-R scores (stereotyped, self-injurious, compulsive, sameness, restricted, sum)(omnibus test, p = 0.002-0.028). Taken together, the A alleles of rs2056202 and rs2292813 were consistently and positively associated with RRB traits in both the UIC-UF and SSC samples, but the most significant SNP with phenotype association varied in each dataset.ConclusionsThis study confirmed an association between SLC25A12 and RRB traits in ASDs, but the direction of the association was different from that in the initial study. This could be due to the examined SLC25A12 SNPs being in linkage disequilibrium with another risk allele, and/or genetic/phenotypic heterogeneity of the ASD samples across studies.

Dataset Information

Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders.

Publications

Evidence for contribution of common genetic variants within chromosome 8p21.2-8p21.1 to restricted and repetitive behaviors in autism spectrum disorders.

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