title: Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.
abstract: Several genome-wide association and candidate gene studies have linked chromosome 15q24-q25.1 (a region including the CHRNA5-CHRNA3-CHRNB4 gene cluster) with alcohol dependence, nicotine dependence and smoking-related illnesses such as lung cancer and chronic obstructive pulmonary disease. To further examine the impact of these genes on the development of substance use disorders, we tested whether variants within and flanking the CHRNA5-CHRNA3-CHRNB4 gene cluster affect the transition to daily smoking (individuals who smoked cigarettes 4 or more days per week) in a cross sectional sample of adolescents and young adults from the COGA (Collaborative Study of the Genetics of Alcoholism) families. Subjects were recruited from families affected with alcoholism (either as a first or second degree relative) and the comparison families. Participants completed the SSAGA interview, a comprehensive assessment of alcohol and other substance use and related behaviors. Using the Quantitative trait disequilibrium test (QTDT) significant association was detected between age at onset of daily smoking and variants located upstream of CHRNB4. Multivariate analysis using a Cox proportional hazards model further revealed that these variants significantly predict the age at onset of habitual smoking among daily smokers. These variants were not in high linkage disequilibrium (0.28<r(2)<0.56) with variants that have previously been reported to affect risk for nicotine dependence and smoking related diseases in adults. The data suggests that an age-associated relationship underlies the association of SNPs in CHRNB4 with onset of chronic smoking behaviors in adolescents and young adults and may improve genetic information that will lead to better prevention and intervention for substance use disorders among adolescents and young adults.
authors.affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.
authors.forename: Manav
authors.initials: M
authors.lastname: Kapoor
authors.forename: Jen-Chyong
authors.initials: JC
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Kathy
authors.initials: K
authors.lastname: Bucholz
authors.forename: John P
authors.initials: JP
authors.lastname: Budde
authors.forename: Anthony
authors.initials: A
authors.lastname: Hinrichs
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Andrew
authors.initials: A
authors.lastname: Brooks
authors.forename: David
authors.initials: D
authors.lastname: Chorlian
authors.forename: Danielle
authors.initials: D
authors.lastname: Dick
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.forename: John
authors.initials: J
authors.lastname: Kramer
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.forename: Niklas
authors.initials: N
authors.lastname: Manz
authors.forename: John
authors.initials: J
authors.lastname: Nurnberger
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.forename: John
authors.initials: J
authors.lastname: Rice
authors.forename: Jay
authors.initials: J
authors.lastname: Tischfield
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000437:Alcoholism / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011978:Receptors, Nicotinic / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000235:genetics* / Q000523:psychology; D055815:Young Adult
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human