title: Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits.
abstract: BACKGROUND
  The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes.
  
  
  METHODS
  The study sample was ascertained from the Finnish Twin Cohort study. Twin pairs born 1938-1957 and concordant for a history of cigarette smoking were recruited along with their family members (mainly siblings), as part of the Nicotine Addiction Genetics consortium. The study sample consisted of 1,428 individuals (59% males) from 735 families, with mean age 55.6 years.
  
  
  RESULTS
  We detected multiple novel associations for ND. DSM-IV ND symptoms associated significantly with the proxy SNP Locus 1 (rs2036527, p = .000009) and Locus 2 (rs578776, p = .0001) and tolerance factor of the Nicotine Dependence Syndrome Scale (NDSS) showed suggestive association to rs11636753 (p = .0059), rs11634351 (p = .0069), and rs1948 (p = .0071) in CHRNB4. Furthermore, we report significant association with DSM-IV ND diagnosis (rs2036527, p = .0003) for the first time in a Caucasian population. Several SNPs indicated suggestive association for traits related to ages at smoking initiation. Also, rs11636753 in CHRNB4 showed suggestive association with regular drinking (p = .0029) and the comorbidity of depression and ND (p = .0034).
  
  
  CONCLUSIONS
  We demonstrate novel associations of DSM-IV ND symptoms and the NDSS tolerance subscale. Our results confirm and extend association findings for other ND measures. We show pleiotropic effects of this gene cluster on multiple measures of ND and also regular drinking and the comorbidity of ND and depression.
authors.affiliation: Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Ulla
authors.initials: U
authors.lastname: Broms
authors.forename: Juho
authors.initials: J
authors.lastname: Wedenoja
authors.forename: Marine R
authors.initials: MR
authors.lastname: Largeau
authors.forename: Tellervo
authors.initials: T
authors.lastname: Korhonen
authors.forename: Janne
authors.initials: J
authors.lastname: Pitkäniemi
authors.forename: Kaisu
authors.initials: K
authors.lastname: Keskitalo-Vuokko
authors.forename: Anja
authors.initials: A
authors.lastname: Häppölä
authors.forename: Katri H
authors.initials: KH
authors.lastname: Heikkilä
authors.forename: Kauko
authors.initials: K
authors.lastname: Heikkilä
authors.forename: Samuli
authors.initials: S
authors.lastname: Ripatti
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Sarin
authors.forename: Outi
authors.initials: O
authors.lastname: Salminen
authors.forename: Tiina
authors.initials: T
authors.lastname: Paunio
authors.forename: Michele L
authors.initials: ML
authors.lastname: Pergadia
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Jaakko
authors.initials: J
authors.lastname: Kaprio
authors.forename: Anu
authors.initials: A
authors.lastname: Loukola
mesh_terms: D017668:Age of Onset; D000483:Alleles; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000235:genetics; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human