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Paul Daniel Arnold, MD; Tricia Sicard, BSc; Eliza Burroughs, BA; Margaret A. Richter, MD; James L. Kennedy, MD

Arch Gen Psychiatry. 2006;63:769-776.

Context  There is strong evidence from family and twin studies that genetic determinants play an important role in the etiology of obsessive-compulsive disorder (OCD). In the only genome scan of OCD to date that we are aware of, suggestive linkage was reported to the chromosomal region 9p24, a finding that was subsequently replicated. This region contains the gene encoding the neuronal glutamate transporter, SLC1A1. SLC1A1 represents an excellent candidate gene for OCD based on evidence from neuroimaging and animal studies that altered glutamatergic neurotransmission is implicated in the pathogenesis of this disorder.

Objective  To determine whether sequence variants in SLC1A1 are associated with transmission of the OCD trait.

Design  A family-based candidate gene association study.

Setting  A specialized anxiety disorders outpatient clinic.

Participants  One hundred fifty-seven white probands with DSM-IV OCD recruited from consecutive referrals and their first-degree relatives (476 individuals in total).

Intervention  Nine single nucleotide polymorphisms spanning SLC1A1 were genotyped. Single-locus and haplotype analyses were performed using the Family-Based Association Test and the Transmission Disequilibrium Test. Traits examined included DSM-IV OCD diagnosis and highest lifetime symptom severity as measured using the Yale-Brown Obsessive-Compulsive Scale. Correction for multiple comparisons was performed using permutation tests.

Results  After correction for multiple comparisons, 2 variants, rs301434 (² = 12.04; P = .006) and rs301435 (² = 9.24; P = .03), located within a single haplotype block were found to be associated with transmission of OCD. Furthermore, a specific 2-marker haplotype within this block was significantly associated with OCD (² = 12.60; P = .005). This haplotype association was statistically significant in transmissions to male but not female offspring.

Conclusions  Although requiring replication in larger samples, these findings provide preliminary evidence that sequence variation in SLC1A1 is associated with susceptibility to OCD, particularly in males. Furthermore, these results provide support for the role of altered glutamatergic neurotransmission in the pathogenesis of OCD.

Author Affiliations: Neurogenetics Section (Drs Arnold and Kennedy and Ms Sicard) and Anxiety Disorders Clinic (Ms Burroughs and Dr Richter), Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario.

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