A non-coding CRHR2 SNP rs255105, a cis-eQTL for a downstream lincRNA AC005154.6, is associated with heroin addiction.
Dysregulation of the stress response is implicated in drug addiction; therefore, polymorphisms in stress-related genes may be involved in this disease. Using samples from CTN-0051 (X:BOT), an analysis was performed to identify associations between variants in 11 stress-related genes, selected a priori, and heroin addiction. Two discovery samples of American subjects of European descent (EA, n = 601) and of African Americans (AA, n = 400) were analyzed separately. Ancestry was verified by principal component analysis. Final sets of 414 (EA) and 562 (AA) variants were analyzed after filtering of 846 high-quality variants. The main result was an association of a non-coding SNP rs255105 in the CRH (CRF) receptor 2 gene (CRHR2), in the discovery EA sample (Pnominal = .00006; OR = 2.1; 95% CI 1.4–3.1). The association signal remained significant after permutation-based multiple testing correction. The result was corroborated by an independent EA case sample (n = 364). Bioinformatics analysis revealed that SNP rs255105 is associated with the expression of a downstream long intergenic non-coding RNA (lincRNA) gene AC005154.6. AC005154.6 is highly expressed in the pituitary but its functions are unknown. LincRNAs have been previously associated with adaptive behavior, PTSD, and alcohol addiction.
Conclusions: Hypothesis-driven study of variants in stress-related genes and heroin addiction identified an association with non-coding SNP in the CRHR2 gene. A downstream lincRNA gene is a ciseQTL of this SNP and additional SNPs in the region. This result is intriguing since lincRNAs play a role in adaptive behavior and neurological diseases and are potential drug targets for stress-related disorders. Further studies are warranted to corroborate the association results and to assess the potential relevance of this lincRNA to addiction and other stress-related disorders.
Related protocols: CTN-0051, CTN-0051-A-1