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Association Testing of the Positional and Functional Candidate Gene SLC1A1/EAAC1 in Early-Onset Obsessive-compulsive Disorder
Diane E. Dickel, BA;
Jeremy Veenstra-VanderWeele, MD;
Nancy J. Cox, PhD;
Xiaolin Wu, MD, PhD;
Daniel J. Fischer, MSW;
Michelle Van Etten-Lee, PhD;
Joseph A. Himle, PhD;
Bennett L. Leventhal, MD;
Edwin H. Cook, Jr, MD;
Gregory L. Hanna, MD
Arch Gen Psychiatry. 2006;63:778-785.
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.
Author Affiliations: Department of Human Genetics, University of Chicago (Ms Dickel and Drs Cox and Wu), and Institute for Juvenile Research, Department of Psychiatry, University of Illinois at Chicago (Drs Veenstra-VanderWeele, Leventhal, and Cook), Chicago, Ill; and Department of Psychiatry, University of Michigan, Ann Arbor (Mr Fischer and Drs Van Etten-Lee, Himle, and Hanna). Ms Dickel is now with the Department of Genome Sciences, University of Washington, Seattle. Dr Veenstra-VanderWeele is now with the Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tenn.
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