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Jens R. Wendland, MD; Pablo R. Moya, PhD; Kiara R. Timpano, MS; Adriana P. Anavitarte, BS; Matthew R. Kruse, BA; Michael G. Wheaton, BA; Renee F. Ren-Patterson, MD, PhD; Dennis L. Murphy, MD

Arch Gen Psychiatry. 2009;66(4):408-416.

Context  Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD).

Objectives  To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality.

Design  A case-control study.

Setting  Publicly accessible SLC1A1 expression and genotype data.

Patients  Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls.

Interventions  Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory–Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation.

Results  Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales.

Conclusions  Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database–mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders.

Author Affiliations: Laboratory of Clinical Science (Drs Wendland, Moya, and Murphy; Ms Anavitarte; and Mssrs Kruse and Wheaton), and Clinical Brain Disorders Branch (Dr Ren-Patterson), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; and Department of Psychology, Florida State University, Tallahassee (Ms Timpano).

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