title: Prediction of the risk of comorbid alcoholism in schizophrenia by interaction of common genetic variants in the corticotropin-releasing factor system.
abstract: BACKGROUND
  Stress plays a major role in the development of comorbid alcohol use disorder (AUD). In turn, AUD worsens the outcome of psychiatric patients with respect to global disease severity, social situation, and socioeconomic burden. Prediction of persons at risk for AUD is crucial for future preventive and therapeutic strategies.
  
  
  OBJECTIVE
  To investigate whether genetic variants of the corticotropin-releasing factor system or their interaction influence the risk of developing AUD in chronic disease populations.
  
  
  METHODS
  Genotype analysis comprising selected single-nucleotide polymorphisms within the CRHR1 and CRHBP genes in patients with schizophrenia and in a nonschizophrenic psychiatric disease control sample should allow the extraction of predictors of comorbid AUD. Gene expression (messenger RNA) analysis in peripheral blood mononuclear cells was performed to gain the first mechanistic insight.
  
  
  METHODS
  An ideal setup for this study was the Göttingen Research Association for Schizophrenia Data Collection of schizophrenic patients, specifically intended to enable association of genetic information with quantifiable phenotypes in a phenotype-based genetic association study. Patients  A total of 1037 schizophrenic patients (Göttingen Research Association for Schizophrenia sample), 80 nonschizophrenic psychiatric disease controls as a small replicate sample, and a case-control study including 1141 healthy subjects.
  
  
  METHODS
  Association of CRHR1 and CRHBP genotypes with the following: (1) AUD; (2) a newly developed alcoholism severity score comprising 5 AUD-relevant variables; and (3) quantitative CRHR1 and CRHBP messenger RNA expression.
  
  
  RESULTS
  An interaction of CRHR1 rs110402 and CRHBP rs3811939 predicts high risk of comorbid AUD in schizophrenic patients (odds ratio = 2.27; 95% confidence interval, 1.56-3.30; P < .001) as well as psychiatric disease controls (odds ratio = 4.02; 95% confidence interval, 0.95-17.05; P = .06) and leads to the highest CRHR1/CRHBP messenger RNA ratio (P = .02; dysbalanced stress axis).
  
  
  CONCLUSIONS
  The high predictive value of a genetic interaction within the stress axis for the risk of comorbid AUD may be used for novel preventive and individualized therapeutic approaches.
authors.affiliation: Division of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Ribbe
authors.forename: Verena
authors.initials: V
authors.lastname: Ackermann
authors.forename: Judith
authors.initials: J
authors.lastname: Schwitulla
authors.forename: Martin
authors.initials: M
authors.lastname: Begemann
authors.forename: Sergi
authors.initials: S
authors.lastname: Papiol
authors.forename: Sabrina
authors.initials: S
authors.lastname: Grube
authors.forename: Swetlana
authors.initials: S
authors.lastname: Sperling
authors.forename: Heidi
authors.initials: H
authors.lastname: Friedrichs
authors.forename: Olaf
authors.initials: O
authors.lastname: Jahn
authors.forename: Inge
authors.initials: I
authors.lastname: Sillaber
authors.forename: Olaf
authors.initials: O
authors.lastname: Gefeller
authors.forename: Henning
authors.initials: H
authors.lastname: Krampe
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015897:Comorbidity; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000502:physiology; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics / Q000503:physiopathology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D002352:Carrier Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; C067133:corticotropin releasing factor-binding protein; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone