Interaction of common genetic variants in the CRF system predicts the risk of comorbid alcoholism

Stress plays a major role in the development of comorbid alcohol use disorder (AUD). AUD in turn worsens the outcome of psychiatric patients with respect to global disease severity, social situation and thus socioeconomic burden. Prediction of persons at-risk of AUD is crucial for future preventive and therapeutic strategies. We investigated whether genetic variants of the corticotropin-releasing factor (CRH) system or their interaction influence the risk of developing AUD in chronic disease populations. Genotype analysis comprising selected single nucleotide polymorphisms (SNPs) within the CRHR1 and CRHBP genes in patients with schizophrenia and in a non-schizophrenic psychiatric disease control sample should allow extracting predictors of comorbid AUD. Gene expression (mRNA) analysis in peripheral blood mononuclear cells (PBMCs) was performed to gain first mechanistic insight. An ideal set-up for the present study was the GRAS (Göttingen Research Association for Schizophrenia) Data Collection of schizophrenic patients, specifically intended to enable association of genetic information with quantifiable phenotypes in a procedure termed PGAS (phenotype-based genetic association study). A total of 1037 schizophrenic patients (GRAS sample) were included, as well as 80 non-schizophrenic psychiatric disease controls as small replicate sample, and 1141 healthy subjects as case control study. Associations of CRHR1 and CRHBP genotypes were determined with: (1) AUD, (2) a here developed alcoholism severity score (ASS; composed of 5 AUD-relevant variables), and (3) quantitative CRHR1 and CRHBP mRNA expression. We found that an interaction of CRHR1 rs110402 and CRHBP rs3811939 predicts high risk of comorbid AUD in schizophrenic patients (odds ratio [OR]= 2.27; 95% CI, 1.56 – 3.30; p < 0.0001) as well as psychiatric disease controls (OR = 4.02; 95% CI, 0.95 – 17.05; p = 0.059) and leads to the highest CRHR1/CRHBP mRNA ratio (p = 0.021; 'dysbalanced' stress axis). The high predictive value of a genetic interaction within the stress axis for the risk of comorbid AUD may be exploited for novel preventive and individualized therapeutic approaches.