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

Kapoor M, Wang JC, Bertelsen S, Bucholz K, Budde JP, Hinrichs A, Agrawal A, Brooks A, Chorlian D, Dick D, Hesselbrock V, Foroud T, Kramer J, Kuperman S, Manz N, Nurnberger J, Porjesz B, Rice J, Tischfield J, Xuei X, Schuckit M, Edenberg HJ, Bierut LJ, Goate AM - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.

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

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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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pone-0033513-g002: 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′).

Mentions: There are many environmental factors such as influence of peer group [28], lack of parental monitoring [29] and easy access to cigarettes can also influence the genetic liability to smoking behavior in young adults. Koopmans et al [30] reported that the total variance accounted by genetic influences on smoking initiation and cigarettes per day is 39% and 86%, respectively. The liability to ever smoking is largely independent from liability to continue to smoke. This could be due to the fact that while over 80% of individuals in some studies report that they have tried smoking cigarettes, only about one third of them will smoke beyond experimentation [31]. Hence genetic factors may have stronger impact on daily smoking (smoked ≥4 days/week) and habitual smoking (one pack a day for 6 months) rather than smoking initiation. Therefore in the present study we focused on subjects ascertained as daily smokers to find out the relationship between CHRNA5-CHRNA3-CHRNB4 variants and onset of daily/habitual smoking behaviors, believing that this selected group can explain more genetic variance than smoking initiation or exposure. We found that the rs1996371 and correlated variants located upstream of CHRNB4 gene were associated with age at onset of daily smoking. Since our sample is multi-ethnic we also restricted our analyses to the largest subgroup (European Americans) to ensure that the association was not a false positive due to heterogeneity in our dataset. The association remained in this subgroup. The association between age at onset of daily smoking and rs1996371 and correlated SNPs also remained statistically significant after correcting for multiple testing proposed by Nyholt et al [25], (rs1996371, p = 0.0058). The daily smokers who had at least one copy of the minor allele of rs1996371 had a mean AAO of daily smoking 1 year younger than individuals without the minor allele. The non-synonymous SNP, rs16969968 was not associated with age at onset of daily smoking. We further wanted to explore whether daily smokers with these variants are at increased risk of becoming habitual smokers in future. Our Cox-proportional hazard analysis indeed showed that smokers who have an early AAO of daily smoking and carry a minor allele of rs1996371 have approximately 1.2 times higher risk of becoming habitual smokers compared to daily smokers who carry the major allele. This association was further confirmed in stratified analysis in EAs (rs1996371, p = 0.03, HR: 1.17). In African Americans the variant was not statistically significant, most likely because of low power, but the effect was in the same direction (rs1996371, p>0.05, HR: 1.21). SNP rs1996371 has low correlation (0.28<r2<0.56 in Europeans using HapMap data, Figure 2) with variants (e.g. rs1051730, rs16969968) that were reported to affect risk for nicotine dependence and smoking related diseases in adults. Interestingly Schlaepfer et al reported a variant in the 3′UTR of CHRNB4 gene, rs1948, has been linked to early age of initiation for tobacco use in an ethnically diverse young adult cohort [32]. They also found that a variant, rs11634351 that is in low LD with rs1948 (r2 = 0.24) had significant association with age at first drink [32]. In current study we found that rs11634351 is associated with AAO of daily smoking and is in complete LD with rs1996371 (Figure 2). High comorbidity among smoking and drinking behaviors might explain this possible overlap [33].


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

Kapoor M, Wang JC, Bertelsen S, Bucholz K, Budde JP, Hinrichs A, Agrawal A, Brooks A, Chorlian D, Dick D, Hesselbrock V, Foroud T, Kramer J, Kuperman S, Manz N, Nurnberger J, Porjesz B, Rice J, Tischfield J, Xuei X, Schuckit M, Edenberg HJ, Bierut LJ, Goate AM - PLoS ONE (2012)

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′).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306405&req=5

pone-0033513-g002: 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′).
Mentions: There are many environmental factors such as influence of peer group [28], lack of parental monitoring [29] and easy access to cigarettes can also influence the genetic liability to smoking behavior in young adults. Koopmans et al [30] reported that the total variance accounted by genetic influences on smoking initiation and cigarettes per day is 39% and 86%, respectively. The liability to ever smoking is largely independent from liability to continue to smoke. This could be due to the fact that while over 80% of individuals in some studies report that they have tried smoking cigarettes, only about one third of them will smoke beyond experimentation [31]. Hence genetic factors may have stronger impact on daily smoking (smoked ≥4 days/week) and habitual smoking (one pack a day for 6 months) rather than smoking initiation. Therefore in the present study we focused on subjects ascertained as daily smokers to find out the relationship between CHRNA5-CHRNA3-CHRNB4 variants and onset of daily/habitual smoking behaviors, believing that this selected group can explain more genetic variance than smoking initiation or exposure. We found that the rs1996371 and correlated variants located upstream of CHRNB4 gene were associated with age at onset of daily smoking. Since our sample is multi-ethnic we also restricted our analyses to the largest subgroup (European Americans) to ensure that the association was not a false positive due to heterogeneity in our dataset. The association remained in this subgroup. The association between age at onset of daily smoking and rs1996371 and correlated SNPs also remained statistically significant after correcting for multiple testing proposed by Nyholt et al [25], (rs1996371, p = 0.0058). The daily smokers who had at least one copy of the minor allele of rs1996371 had a mean AAO of daily smoking 1 year younger than individuals without the minor allele. The non-synonymous SNP, rs16969968 was not associated with age at onset of daily smoking. We further wanted to explore whether daily smokers with these variants are at increased risk of becoming habitual smokers in future. Our Cox-proportional hazard analysis indeed showed that smokers who have an early AAO of daily smoking and carry a minor allele of rs1996371 have approximately 1.2 times higher risk of becoming habitual smokers compared to daily smokers who carry the major allele. This association was further confirmed in stratified analysis in EAs (rs1996371, p = 0.03, HR: 1.17). In African Americans the variant was not statistically significant, most likely because of low power, but the effect was in the same direction (rs1996371, p>0.05, HR: 1.21). SNP rs1996371 has low correlation (0.28<r2<0.56 in Europeans using HapMap data, Figure 2) with variants (e.g. rs1051730, rs16969968) that were reported to affect risk for nicotine dependence and smoking related diseases in adults. Interestingly Schlaepfer et al reported a variant in the 3′UTR of CHRNB4 gene, rs1948, has been linked to early age of initiation for tobacco use in an ethnically diverse young adult cohort [32]. They also found that a variant, rs11634351 that is in low LD with rs1948 (r2 = 0.24) had significant association with age at first drink [32]. In current study we found that rs11634351 is associated with AAO of daily smoking and is in complete LD with rs1996371 (Figure 2). High comorbidity among smoking and drinking behaviors might explain this possible overlap [33].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri, United States of America.

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

Show MeSH
Related in: MedlinePlus