Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples

Abstract

To investigate the role of the corticotropin releasing hormone receptor 1 (CRHR1) in patterns of human alcohol drinking and its potential contribution to alcohol dependence, we analysed two independent samples: a sample of adolescents, which consisted of individuals from the 'Mannheim Study of Risk Children' (MARC), who had little previous exposure to alcohol, and a sample of alcohol-dependent adults, who met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the CRHR1 gene, two haplotype tagging (ht)SNPs discriminating between haplotypes with a frequency of X0.7% were identified. Both samples were genotyped and systematically examined for association with the htSNPs of CRHR1. In the adolescent sample, significant group differences between genotypes were observed in binge drinking, lifetime prevalence of alcohol intake and lifetime prevalence of drunkenness. The sample of adult alcohol-dependent patients showed association of CRHR1 with high amount of drinking. This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported. Our findings support results from animal models, suggesting an importance of CRHR1 in integrating geneenvironment effects in alcohol use disorders.

Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking

“…Circadian and stress-response systems are important physiologic mediators of environmental influences. In research on alcohol dependence, stress-related gene-by-environment interactions have been described (1), and one prominent example relates to the finding that CRHR1 moderates the effect of psychosocial stress on alcohol consumption in rodent animal models (20,24) as well as in humans (25,26). In the present article, we show that psychosocial stress moderates the effect of circadian rhythm gene Per1 on excessive alcohol drinking.…”

“…The rs3027172 genotype might be involved in cortisol-induced genotype-specific transcriptional activation of hPer1, which is mediated in part by the transcription factor Snail1. Although the interpretation of gene-by-environment interaction in genetic association studies is complicated by the fact that environmental and genetic components are bi-directionally interconnected (i.e., the environment and the individual affect each other) (25,26), our in vitro and in vivo functional genetic analyses suggest that the effects of exposure to psychosocial stress on risky alcohol consumption are mediated in part by variation in the Per1 gene.…”

Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress

“…Based on an analysis of 14 human Crhr1 polymorphisms, two haplotype tagging SNPs were recently identified and examined for association with drinking phenotypes. In an adolescent sample, association was observed with binge drinking, lifetime prevalence of alcohol intake, and lifetime prevalence of drunkenness; whereas in a sample of adult alcohol- dependent patients, an association was found with high amount of drinking (19). Together with these findings, our data suggest that CRH-R1 antagonists may be useful for treatment of alcoholism, and particularly so in carriers of susceptibility alleles at the Crhr1 locus, in analogy with data emerging for a functional variant of the -opioid receptor (20,21).…”

FKBP5 and CRHR1 polymorphisms moderate the stress–physical health association in a national sample.

“…Second, studies have also implicated CRHR1 SNPs in heavy alcohol use during adolescence (Blomeyer et al, 2008) and binge drinking (Treutlein et al, 2006), and CRHR1 gene upregulation has been linked to the risk of relapse after cessation of drinking (Sommer et al, 2008). CRHR1 SNPs also interact with stressful life events to predict heavy drinking among 19-year-olds (Schmid et al, 2010).…”