TACR1 Genotypes Predict fMRI Response to Alcohol Cues and Level of Alcohol Dependence

Background The tachykinin receptor 1 (TACR1) gene is a promising candidate gene in the search for the genetic basis of alcohol dependence (AD); TACR1 antagonists improve symptomology not only in preclinical models of AD but also in a clinical sample of detoxified alcoholics (George et al., Science 319:1536, 2008). The purpose of the current study was to determine whether TACR1 single nucleotide polymorphisms (SNPs) were associated with (i) blood oxygen level dependent (BOLD) activation in response to gustatory alcohol cues in a sample of heavy drinkers and (ii) Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) AD symptom count in a large, publicly available data setthe Study of Addictions: Genetics and Environment Genome Wide Association study (SAGE GWAS) (Bierut et al., 2010). Methods First, we examined relationships between TACR1 genotypes and neural responses during a craving task in 326 individuals with alcohol use disorders. Next, correlational analyses between 69 TACR1 SNPs and DSM-IV-TR AD symptoms were performed on the SAGE data set. Results rs3771863, rs3755459, and rs1106855 predicted BOLD activation in response to alcohol cues in those same reward and reinforcement brain areas, especially in the medial prefrontal cortex, striatum, and insula. rs3771863 also predicted AD symptom count in the SAGE data set and BOLD activation in the mesocorticolimbic pathway response to alcohol cues. Conclusions Each of the 5 SNPs in the TACR1 gene that was significantly related to AD severity in the SAGE data set and/or the BOLD response to the craving task is near the 3' or 5' areas of the gene and may therefore be near mutations with potential functional significance. In particular, the potential functional significance of rs1106855 should be explored because of its location within a stop codon.