Background: SLC25A12 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). Methods. We 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). Results: In 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. Conclusions: This 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.
Bibliographical noteFunding Information:
We extend our sincere gratitude to all of the families at our research clinics (UIC and UF) and at the participating SFARI Simplex Collection (SSC) sites. We are grateful to the SSC Genetics Committee and the principal investigators (A Beaudet, R Bernier, J Constantino, E Cook, E Fombonne, D Geschwind, D Grice, A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley, B Peterson, J Piggot, C Saulnier, M State,W Stone, J Sutcliffe, C Walsh, and E Wijsman). We appreciate obtaining access to phenotypic and genetic data on SFARI Base. Approved researchers can obtain the SSC population dataset described in this study (include here the URL of the population used, obtained from SFARI Base) by applying at https://sfari.org/sfari-base. We gratefully acknowledge Emily Wray, Lindsay Bell and Susan Craft for their expert assistance, Sunday Francis for her critical review of this manuscript, and the UF Child and Adolescent Psychiatry fellows and the staff of the UF Center for Autism and Related Disabilities (CARD) for their assistance with recruitment. This work was supported in part by a 2007 NARSAD young investigator award (SJK), the 2008 PWSA (USA) Research Award (SJK), NIH R03MH083673 (SJK), NIH K23MH082883 (SJK), NIH K23MH082121 (SJ), NIH Autism Center of Excellence P50 HD055751 (EHC) and NIH/National Center for Research Resources (NCRR) CTSA grant 1UL 1RR029890.