A novel, putative gain-of-function haplotype at SLC6A4 associates with obsessive-compulsive disorder

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