Genetic Investigation of Insistence on Sameness in Autism

Background: Restricted and repetitive behaviors (RRBs), in conjunction with social and communication problems, are defining features of the neurodevelopmental conditions that comprise the autism spectrum. The RRBs are generally grouped into two subdomains: insistence on sameness (IS) and repetitive sensory motor behaviors (RSMB). IS is the more robust of the domains and appears to be independent of developmental level, reducing potential overlap with intellectual disability phenotype. To date, there has been limited study of the genetic basis for the IS trait.

Objectives: For this study, we propose to test for genetic association with IS in a large sample of individuals with autism for whom we have targeted sequence data. We hypothesize that multiple genetic variants will be associated with the IS score.

Methods: Using Autism Diagnostic Interview-Revised (ADI-R) items, we calculated IS scores for our dataset of 1931 participants from the Hussman Institute for Human Genomics and Simons Simplex Collection. The items making up the IS trait include difficulties with minor changes, resistance to trivial changes, abnormal response to sensory stimuli, circumscribed interests, compulsions/rituals, sensitivity to noise. All individuals were sequenced with a 17Mb custom capture covering 681 genes within regions identified by GWAS of ASD. We conducted the SKAT-O gene-based test and single variant tests using IS scores as continuous outcomes. A Bonferroni correction for the number of genes tested was used as a significance threshold.

Results: For the gene-based test our top four results were: ATXN1, ARHGAP40, BICD1 and GCOM1 with p-values of 5.6E-03, 5.8E-03, 6.2E-03 and 7E-03, respectively. When only missense variants were analyzed, the top three genes were PANK1, TIMM22 and ZNF397with p-values of 1E-02, 1.2E-02 and 1.3E-02 respectively. ATXN1 is located on the short arm of chromosome 6, it is a protein coding gene and is associated with spinocerebellar ataxia type 1 (SCA 1). ZNF397 is located on the long arm of chromosome 18 and is part of the zing finger family. This gene is well established for its role in and has shown prior association with ASD. Overall, we identified 32 genes with p-values of less than 0.05.

Conclusions: We did not find genome-wide association to the IS trait in our dataset. Our top nominally significant results suggest a possible role of several genes in the modification of the IS trait in individuals with ASD but need further investigation. We propose that the current findings serve as a first step in dissecting the genetic basis of the IS trait in ASD. Within this group of individuals there is still substantial phenotypic heterogeneity which hinders our ability to detect association. With respect to the current results, we would propose follow up studies that focus on the sequence of the reported genes and surrounding areas. More generally, our results suggest the value of identifying genes associated with phenotypic traits that are a part of ASD as an alternative to using the broader ASD diagnostic phenotype.