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

Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 01/2008; 32(12):2543-51. DOI: 10.1038/sj.npp.1301394
Source: PubMed


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=347) and controls (N=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 x 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.

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    • "The BDNF Val66Met polymorphism (dbSNP rs6265) was genotyped by a 5'-exonuclease assay (TaqMan SNP genotyping assay-on-demand; Applied Biosystems, Foster City, CA, USA) using oligonucleotide primers GCC CAA GGC AGG TTC AAG AG and AAC TTT CTG GTC CTC ATC CAA CAG as well as fluorescent probes VIC-ACT TTC GAA CAC gTG ATA G-MGB and FAM-CTT TCG AAC ACa TGA TAG-MGB for Val66 and Met66, respectively, as reported previously (Wendland, et al., 2007). In a total reaction volume of 8 µL, 5–20 ng of genomic DNA were mixed with TaqMan Universal PCR master mix (Applied Biosystems) and genotyping assay to 1× final concentrations. "
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    ABSTRACT: The gene coding for the brain derived neurotrophic factor (BDNF) has emerged as an interesting candidate for multiple brain and brain disorder-related phenomena. The primary aim of the present investigation was to consider the relationship between the BDNF Val66Met variant and two phenotypes: compulsive hoarding as a symptom dimension of obsessive-compulsive disorder (OCD), and body mass index (BMI). We examined the BDNF gene in a large (N=301) clinical sample of probands with OCD. Participants were classified as hoarding or nonhoarding using a strict, multimeasure grouping approach. Results revealed that the Val/Val genotype was linked with hoarding classification and more severe hoarding behaviors, as well as greater BMI levels. Hoarding status was also associated with greater BMI scores, with individuals in the hoarding group being far more likely to be classified as obese compared with the nonhoarding group. Our findings may provide a distinct avenue through which hoarding and BMI could be linked. These findings are suggestive of a complex gene, body weight, and psychopathology relationship wherein a primitive, survival "thrifty gene" strategy may be conserved and represented in a subgroup of humans manifesting severe hoarding symptoms.
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    • "Replication in a large case-control design was unable to corroborate this, although an increased frequency of the LA allele and LALA genotype in OCD probands was observed21. Wendland et al22 reported a highly significant haplotype-based omnibus association of all the known non-coding functional SLC6A4 variants with OCD in a large case-control sample. "
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    The Indian Journal of Medical Research 12/2010; 132(6):690-5. · 1.40 Impact Factor
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    • "Some evidence suggests that the effect of the 5-HTTLPR genotype on the serotonin transporter gene expression is further influenced by a polymorphism of the 5-HTTLPR long allele (rs25531), but we did not genotype this variant. However, several studies that genotyped the rs25531 polymorphism have found no association with neuroticism, anxiety, depression, or obsessive compulsive disorder (Gunthert et al, 2007; Wachleski et al, 2008; Wendland et al, 2007; Wray et al, 2009). "
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met x 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.
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