Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.
- Authors
- Kapoor, Manav; Wang, Jen-Chyong; Bertelsen, Sarah; Bucholz, Kathy; Budde, John P; Hinrichs, Anthony; Agrawal, Arpana; Brooks, Andrew; Chorlian, David; Dick, Danielle; Hesselbrock, Victor; Foroud, Tatiana; Kramer, John; Kuperman, Samuel; Manz, Niklas; Nurnberger, John; Porjesz, Bernice; Rice, John; Tischfield, Jay; Xuei, Xiaoling; Schuckit, Marc; Edenberg, Howard J; Bierut, Laura J; Goate, Alison M
- Year
- 2012
- Journal
- PloS one
- PMID
- 22438940
- DOI
- 10.1371/journal.pone.0033513
- PMCID
- PMC3306405
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.
Genotypes of rs1996371 significantly predict age at onset of habitual smoking.
Linkage disequilibrium between genotyped SNPs.Number in each square represents the a pairwise LD relationship (r2) between the two SNP's in Caucasians using HapMap data and varying red color represent the linkage disequilibrium values for that pair as measured by D′ (bright red shows high D′).
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