Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent

Jadwiga Buchwald, Meghan J. Chenoweth, Teemu Palviainen, Gu Zhu, Christian Benner, Scott Gordon, Tellervo Korhonen, Samuli Ripatti, Pamela A.F. Madden, Terho Lehtimäki, Olli T. Raitakari, Veikko Salomaa, Richard J. Rose, Tony P. George, Caryn Lerman, Matti Pirinen, Nicholas G. Martin, Jaakko Kaprio, Anu Loukola, Rachel F. Tyndale

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Smoking behaviors, including amount smoked, smoking cessation, and tobacco-related diseases, are altered by the rate of nicotine clearance. Nicotine clearance can be estimated using the nicotine metabolite ratio (NMR) (ratio of 3′hydroxycotinine/cotinine), but only in current smokers. Advancing the genomics of this highly heritable biomarker of CYP2A6, the main metabolic enzyme for nicotine, will also enable investigation of never and former smokers. We performed the largest genome-wide association study (GWAS) to date of the NMR in European ancestry current smokers (n = 5185), found 1255 genome-wide significant variants, and replicated the chromosome 19 locus. Fine-mapping of chromosome 19 revealed 13 putatively causal variants, with nine of these being highly putatively causal and mapping to CYP2A6, MAP3K10, ADCK4, and CYP2B6. We also identified a putatively causal variant on chromosome 4 mapping to TMPRSS11E and demonstrated an association between TMPRSS11E variation and a UGT2B17 activity phenotype. Together the 14 putatively causal SNPs explained ~38% of NMR variation, a substantial increase from the ~20 to 30% previously explained. Our additional GWASs of nicotine intake biomarkers showed that cotinine and smoking intensity (cotinine/cigarettes per day (CPD)) shared chromosome 19 and chromosome 4 loci with the NMR, and that cotinine and a more accurate biomarker, cotinine + 3′hydroxycotinine, shared a chromosome 15 locus near CHRNA5 with CPD and Pack-Years (i.e., cumulative exposure). Understanding the genetic factors influencing smoking-related traits facilitates epidemiological studies of smoking and disease, as well as assists in optimizing smoking cessation support, which in turn will reduce the enormous personal and societal costs associated with smoking.

Original languageEnglish
Pages (from-to)2212-2223
Number of pages12
JournalMolecular Psychiatry
Issue number6
StatePublished - Jun 2021


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