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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.

Obsessive-compulsive disorder (OCD) is a disabling neuropsychiatric illness with strong segregation data indicative of major genetic contributions. Association analyses of common functional variants of the serotonin transporter gene (SLC6A4), a long-standing OCD candidate, have so far been inconsistent. Here, we set out to investigate the role of additional functional SLC6A4 loci in OCD. We describe a common, functional C > T single nucleotide polymorphism, rs25532, located less than 150 nucleotides centromeric of the serotonin transporter-linked polymorphic region indel known as 5-HTTLPR. The minor allele of rs25532 significantly decreased luciferase reporter gene expression levels by 15-80%, depending on 5-HTTLPR allele background and cell type. Haplotype-based testing of rs25532 and all other known non-coding functional SLC6A4 variants revealed a highly significant omnibus association with OCD in a large case-control sample. Remarkably, the haplotype significantly overrepresented in probands contained the higher-expressing allele at each locus, supporting the notion of increased serotonin transporter functioning being pathogenetically involved in OCD. Conditional haplotype analyses with the software WHAP revealed that this association is primarily driven by 5-HTTLPR, rs25532 and rs16965628. Our results contribute to a better understanding of SLC6A4 expression genetics and provide a functional haplotype framework for future serotonin-related studies.

Both serotonin transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) genes have shown positive associations with obsessive-compulsive disorder (OCD) and some other psychiatric disorders, but these results have not been consistently replicated. To explore the hypothesis that this variability might result from the effects of differing combinations of overlooked variants within SLC6A4 together with small OCD and control sample sizes, we studied three common functional polymorphisms (5-HTTLPR, STin2, and the newly discovered SNP, rs25531) in the largest sample size of OCD patients (N ¼ 347) and controls (N ¼ 749) ever investigated. During methods development, we found evidence for potential SLC6A4 genotyping problems with earlier methodology, a third possible contributor to variability in earlier studies. A fourth possible explanation might be SLC6A4 Â BDNF interactions, which prompted us to investigate combined genotypes of BDNF V66M with the three SLC6A4 loci. Except for a nominal association with rs25531 alone, which did not survive correction for multiple comparisons, we found no evidence for any of these other variants being associated alone or together with OCD, and we therefore also examined clinical OCD subtypes within the sample to evaluate clinical heterogeneity. Subgroups based on the age of OCD onset, gender, familiality, factor analysis-derived symptom dimensions, or comorbidity with other psychiatric disorders failed to identify SLC6A4-or BDNF-associated phenotypes, with one exception of overall number of comorbid anxiety disorders being significantly associated with 5-HTTLPR/rs25531. We conclude that despite their attractiveness as candidate genes in OCD, our data provide no support for association in this large OCD patient sample and point toward the need to examine other genes as candidates for risk determinants in OCD.