Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder.

Dickel DE, Veenstra-VanderWeele J, Cox NJ, Wu X, Fischer DJ, Van Etten-Lee M, Himle JA, Leventhal BL, Cook EH, Hanna GL
Arch Gen Psychiatry. 2006 63 (7): 778-85

PMID: 16818867 · DOI:10.1001/archpsyc.63.7.778

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.

MeSH Terms (21)

Adolescent Adult Aged Age Factors Age of Onset Child Chromosome Mapping Excitatory Amino Acid Transporter 3 Female Gene Frequency Genetic Predisposition to Disease Genotype Haplotypes Humans Linkage Disequilibrium Male Middle Aged Obsessive-Compulsive Disorder Pedigree Polymorphism, Single Nucleotide Sex Factors

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