A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

Abstract

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.

Gender differences in obsessive-compulsive disorder: a literature review

“…On the other hand, OCD in women, but not in men, was associated with the A allele of the -1438G>A polymorphism of the promoter region of 5-HT2A 50 and the short allele of 5-HTTLPR. 51 However Wendland et al 52 found no association between OCD, gender and three other functional polymorphisms of the serotonin transporter gene (5-HTTLPR, STin2, and rs25531), 52 despite using a larger sample than the one used by Denys et al, 53 which also found an association between the short allele of 5-HTTLPR and women with OCD. 53 Dickel et al 54 also found an association between woman with OCD and the 5-HTTLPR long allele polymorphism, although, after correction for multiple testing, the finding lost significance.…”

“…Wendland et al 52 and Dickel et al 54 found no association between BDNF gene polymorphism and OCD, even after gender stratification. 52,54 However, Alonso et al 70 in a sample of 215 OCD patients and 342 controls, found a significant association between the SNP (rs2378672) in the BDNF receptor gene (neurotrophic tyrosine kinase receptor type 2-NTRK2) and OCD in women (p < 0.0001).…”

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

“…21,22 The mean ± SD of total YBOCS scores was 22.4 ± 0.5, and there were no subgroup differences for the different OCD subgroups considered (including the OCD subgroups with identified CDH2 variants). TD probands and relatives (N ¼ 454) were evaluated by an experienced child psychiatrist based upon TD-related rating scales, as described elsewhere.…”

BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder

“…In an extension of our study, Katerberg et al (2009) observed an association between female Met-allele carriers and less severe http://repository.uwc.ac.za 3 OCD. However, Dickel et al (2007), Wendland et al (2007), Alonso et al (2008) and Tukel et al (2012) found no association between BDNF Val66Met and OCD.…”