Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.

Manav Kapoor,Samuel Kuperman,Tatiana Foroud,Bernice Porjesz,Laura J Bierut,Sarah Bertelsen,John Kramer,Niklas Manz,Arpana Agrawal,Xiaoling Xuei,Victor Hesselbrock,Howard J Edenberg,Alison M Goate,Kathleen K Bucholz ,John P Rice ,Marc A Schuckit ,David B Chorlian ,Anthony L Hinrichs ,John Budde ,Jay A Tischfield ,Jen Chyong Wang ,Danielle M Dick ,John I Nürnberger ,Andrew I Brooks

doi:10.1371/journal.pone.0033513

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<r2<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.

Highlights

Cigarette smoking is a common addictive disorder
Variants located upstream of CHRNB4 are significantly associated with age at onset of daily smoking using Quantitative trait disequilibrium test (QTDT) analysis
Conditional analysis showed that association of rs1996371 and correlated SNPs with age at onset (AAO) of daily smoking is independent of rs16969968 (Table 2)

Summary

Introduction

Cigarette smoking is a common addictive disorder. A recent Surgeon General’s report indicates that one-third of people who have tried smoking become daily smokers [1]. Antismoking campaigns have reduced cigarette use in recent years, the long-term decline of smoking came to a halt in 2010, especially among high school students. In 2010, both 8th and 10th graders showed evidence of an increase in smoking and approximately one in five high school students and adults in the United States continue to smoke regularly [1]. In the United States, cigarette smoking accounts for 30% of all cancer deaths and for nearly 80% of deaths from chronic obstructive pulmonary disease [2,3]. It is the primary causal factor for early cardiovascular disease and deaths [2]

Methods

Results

Conclusion