title: Rare ADH variant constellations are specific for alcohol dependence.
abstract: OBJECTIVE
  Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference.
  
  
  METHODS
  A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis.
  
  
  RESULTS
  We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons.
  
  
  CONCLUSIONS
  We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, West Haven, CT 06516, USA.
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.forename: Robert T
authors.initials: RT
authors.lastname: Malison
authors.forename: Chiang-Shan R
authors.initials: CS
authors.lastname: Li
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.forename: Lingeng
authors.initials: L
authors.lastname: Lu
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Wang
authors.forename: John H
authors.initials: JH
authors.lastname: Krystal
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000437:Alcoholism / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D001315:Australia; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D000426:Alcohol Dehydrogenase