title: Genetic markers of comorbid depression and alcoholism in women.
abstract: BACKGROUND
  Alcohol dependence (AD) is often accompanied by comorbid depression. Recent clinical evidence supports the benefit of subtype-specific pharmacotherapy in treating the population of alcohol-dependent subjects with comorbid major depressive disorder (MDD). However, in many alcohol-dependent subjects, depression is a reactive response to chronic alcohol use and withdrawal and abates with a period of abstinence. Genetic markers may distinguish alcohol-dependent subjects with MDD not tied chronologically and etiologically to their alcohol consumption. In this work, we investigated the association of adenylyl cyclase genes (ADCY1-9), which are implicated in both AD and mood disorders, with alcoholism and comorbid depression.
  
  
  METHODS
  Subjects from Vienna, Austria (n = 323) were genotyped, and single nucleotide polymorphisms (1,152) encompassing the genetic locations of the 9 ADCY genes were examined. The Vienna cohort contained alcohol-dependent subjects differentiated using the Lesch Alcoholism Typology. In this typology, subjects are segregated into 4 types. Type III alcoholism is distinguished by co-occurrence of symptoms of depression and by affecting predominantly females.
  
  
  RESULTS
  We identified 4 haplotypes associated with the phenotype of Type III alcoholism in females. One haplotype was in a genomic area in proximity to ADCY2, but actually within a lincRNA gene, 2 haplotypes were within ADCY5, and 1 haplotype was within the coding region of ADCY8. Three of the 4 haplotypes contributed independently to Type III alcoholism and together generated a positive predictive value of 72% and a negative predictive value of 78% for distinguishing women with a Lesch Type III diagnosis versus women designated as Type I or II alcoholics.
  
  
  CONCLUSIONS
  Polymorphisms in ADCY8 and ADCY5 and within a lincRNA are associated with an alcohol-dependent phenotype in females, which is distinguished by comorbid signs of depression. Each of these genetic locations can rationally contribute to the polygenic etiology of the alcoholism/depression phenotype, and the use of these genetic markers may aid in choosing appropriate and beneficial treatment strategies.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Daniela O
authors.initials: DO
authors.lastname: Procopio
authors.forename: Laura M
authors.initials: LM
authors.lastname: Saba
authors.forename: Henriette
authors.initials: H
authors.lastname: Walter
authors.forename: Otto
authors.initials: O
authors.lastname: Lesch
authors.forename: Katrin
authors.initials: K
authors.lastname: Skala
authors.forename: Golda
authors.initials: G
authors.lastname: Schlaff
authors.forename: Lauren
authors.initials: L
authors.lastname: Vanderlinden
authors.forename: Peter
authors.initials: P
authors.lastname: Clapp
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hoffman
authors.forename: Boris
authors.initials: B
authors.lastname: Tabakoff
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000437:Alcoholism / Q000145:classification / Q000150:complications / Q000235:genetics*; D003865:Major Depressive Disorder / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D062085:RNA, Long Noncoding; D000262:Adenylyl Cyclases; C118292:adenylyl cyclase 8; C419510:adenylyl cyclase type V