An Exome-Wide Association Study Identifies New Susceptibility Loci for Age of Smoking Initiation in African- and European-American Populations

Overview

Journal Nicotine Tob Res

Publisher Oxford University Press

Specialty Public Health

Date 2017 Dec 8

PMID 29216386

Citations 5

Authors

Keran Jiang

Zhongli Yang

Wenyan Cui

Kunkai Su

Jennie Z Ma

Thomas J Payne

Ming D Li

Affiliations

Soon will be listed here.

Abstract

Introduction: Cigarette smoking is one of the largest causes of preventable death worldwide. This study aimed to identify susceptibility loci for age at smoking initiation (ASI) by performing an exome-wide association analysis.

Methods: A total of 2510 smokers of either African-American (AA) or European-American (EA) origin were genotyped and analyzed at both the single nucleotide polymorphism (SNP) and gene levels. After removal of those SNPs with a minor allele frequency (<0.01), 48091 and 34933 SNPs for AAs and EAs, respectively, were used to conduct a SNP-based association analysis. Gene-based analyses were then performed for all SNPs examined within each gene. Further, we estimated the proportion of variance explained by all common SNPs included in the analysis.

Results: The strongest signals were detected for SNPs rs17849904 in the pitrilysin metallopeptidase 1 gene (PITRM1) in the AA sample (p = 9.02 × 10-7) and rs34722354 in the discoidin domain of the receptor tyrosine kinase 2 gene (DDR2) in the EA sample (p = 9.74 × 10-7). Both SNPs remained significant after Bonferroni correction for the number of SNPs tested. Subsequently, the gene-based association analysis revealed a significantly associated gene, DHRS7, in the AA sample (p = 5.00 × 10-6), a gene previously implicated in nicotine metabolism.

Conclusions: Our study revealed two susceptibility loci for age of smoking initiation in the two ethnic samples, with the first being PITRM1 for AA smokers and the second DDR2 for EA smokers. In addition, we found DHRS7 to be a plausible candidate for ASI in the AA sample from our gene-based association analysis.

Implications: PITRM1 and DHRS7 for African-American smokers and DDR2 for European-American smokers are new candidate genes for smoking initiation. These genes represent new additions to smoking initiation, an important but less studied phenotype in nicotine dependence research.

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References

Falkevall A, Alikhani N, Bhushan S, Pavlov P, Busch K, Johnson K . Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006; 281(39):29096-104. DOI: 10.1074/jbc.M602532200. View

van Duijn C, Havekes L, Van Broeckhoven C, de Knijff P, Hofman A . Apolipoprotein E genotype and association between smoking and early onset Alzheimer's disease. BMJ. 1995; 310(6980):627-31. PMC: 2549007. DOI: 10.1136/bmj.310.6980.627. View

Strasser A, Malaiyandi V, Hoffmann E, Tyndale R, Lerman C . An association of CYP2A6 genotype and smoking topography. Nicotine Tob Res. 2007; 9(4):511-8. DOI: 10.1080/14622200701239605. View

Sartor C, Jackson K, McCutcheon V, Duncan A, Grant J, Werner K . Progression from First Drink, First Intoxication, and Regular Drinking to Alcohol Use Disorder: A Comparison of African American and European American Youth. Alcohol Clin Exp Res. 2016; 40(7):1515-23. PMC: 4930366. DOI: 10.1111/acer.13113. View

Huang H, Chanda P, Alonso A, Bader J, Arking D . Gene-based tests of association. PLoS Genet. 2011; 7(7):e1002177. PMC: 3145613. DOI: 10.1371/journal.pgen.1002177. View

Ray R, Tyndale R, Lerman C . Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J Neurogenet. 2009; 23(3):252-61. PMC: 3772540. DOI: 10.1080/01677060802572887. View

Chelala C, Khan A, Lemoine N . SNPnexus: a web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics. 2008; 25(5):655-61. PMC: 2647830. DOI: 10.1093/bioinformatics/btn653. View

Kendler K, Myers J, Damaj M, Chen X . Early smoking onset and risk for subsequent nicotine dependence: a monozygotic co-twin control study. Am J Psychiatry. 2013; 170(4):408-13. PMC: 3615117. DOI: 10.1176/appi.ajp.2012.12030321. View

Horimoto A, Oliveira C, Giolo S, Soler J, de Andrade M, Krieger J . Genetic analyses of smoking initiation, persistence, quantity, and age-at-onset of regular cigarette use in Brazilian families: the Baependi Heart Study. BMC Med Genet. 2012; 13:9. PMC: 3395823. DOI: 10.1186/1471-2350-13-9. View

10.

Li M, Cheng R, Ma J, Swan G . A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction. 2002; 98(1):23-31. DOI: 10.1046/j.1360-0443.2003.00295.x. View

11.

Stambergova H, Skarydova L, Dunford J, Wsol V . Biochemical properties of human dehydrogenase/reductase (SDR family) member 7. Chem Biol Interact. 2013; 207:52-7. DOI: 10.1016/j.cbi.2013.11.003. View

12.

Benowitz N, St Helen G, Dempsey D, Jacob 3rd P, Tyndale R . Disposition kinetics and metabolism of nicotine and cotinine in African American smokers: impact of CYP2A6 genetic variation and enzymatic activity. Pharmacogenet Genomics. 2016; 26(7):340-50. PMC: 4892970. DOI: 10.1097/FPC.0000000000000222. View

13.

Petersen A, Alvarez C, DeClaire S, Tintle N . Assessing methods for assigning SNPs to genes in gene-based tests of association using common variants. PLoS One. 2013; 8(5):e62161. PMC: 3669368. DOI: 10.1371/journal.pone.0062161. View

14.

Loukola A, Wedenoja J, Keskitalo-Vuokko K, Broms U, Korhonen T, Ripatti S . Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. Mol Psychiatry. 2013; 19(5):615-24. PMC: 3883996. DOI: 10.1038/mp.2013.72. View

15.

Yang J, Wang S, Yang Z, Hodgkinson C, Iarikova P, Ma J . The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry. 2014; 20(11):1467-78. PMC: 4452458. DOI: 10.1038/mp.2014.156. View

16.

Han S, Gelernter J, Luo X, Yang B . Meta-analysis of 15 genome-wide linkage scans of smoking behavior. Biol Psychiatry. 2009; 67(1):12-9. PMC: 2975396. DOI: 10.1016/j.biopsych.2009.08.028. View

17.

Li M . The genetics of smoking related behavior: a brief review. Am J Med Sci. 2003; 326(4):168-73. DOI: 10.1097/00000441-200310000-00003. View

18.

Ng P, Henikoff S . SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003; 31(13):3812-4. PMC: 168916. DOI: 10.1093/nar/gkg509. View

19.

Rosenberg N, Huang L, Jewett E, Szpiech Z, Jankovic I, Boehnke M . Genome-wide association studies in diverse populations. Nat Rev Genet. 2010; 11(5):356-66. PMC: 3079573. DOI: 10.1038/nrg2760. View

20.

Skarydova L, Zverinova M, Stambergova H, Wsol V . A simple identification of novel carbonyl reducing enzymes in the metabolism of the tobacco specific carcinogen NNK. Drug Metab Lett. 2013; 6(3):174-81. DOI: 10.2174/1872312811206030004. View