Association Testing of the Positional and Functional Candidate Gene SLC1A1/EAAC1 in Early-Onset Obsessive-compulsive Disorder

Abstract

CONTEXT: The first 2 independent linkage studies for obsessive-compulsive disorder (OCD) identified a region on 9p24 with suggestive evidence for linkage. The glutamate transporter gene solute carrier family 1, member 1 (SLC1A1) is a promising functional candidate in this region because altered glutamatergic concentrations have been found in the striatum and anterior cingulate in neuroimaging studies of pediatric OCD. OBJECTIVE: To determine whether genotypes at polymorphisms in the SLC1A1 gene region are associated with early-onset OCD. DESIGN: Family-based analysis of association using the transmission disequilibrium test, confirmed using the family-based association test. SETTING: Anxiety disorders program in an academic medical center. PARTICIPANTS: Seventy-one probands with DSM-III-R or DSM-IV OCD and their parents. METHODS: Nine single nucleotide polymorphisms spaced throughout the SLC1A1 gene region were genotyped. RESULTS: Significant association was detected at rs3780412 (P = .04) and rs301430 (P = .03), 2 common adjacent single nucleotide polymorphisms in the 3' region of SLC1A1. Analysis by sex revealed that association at rs3780412 was limited to male probands (P = .002). Significant association was also detected for the T/C haplotype at rs301430-rs301979 (P = .03), the only haplotype block identified among the 9 single nucleotide polymorphisms. Analysis by sex also revealed that the haplotype association was limited to male probands (P = .003). A deletion in the 3' flanking region of SLC1A1 was also detected that imperfectly segregated with OCD in a large, multigenerational family with multiple affected individuals. CONCLUSIONS: The 3' region of SLC1A1 may contain a susceptibility allele for early-onset OCD, with differential effects in males and females. The results also provide further support for the involvement of a glutamatergic dysfunction in the pathogenesis of early-onset OCD.