Journal
MOLECULAR PSYCHIATRY
Volume 26, Issue 6, Pages 2212-2223Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-020-0702-z
Keywords
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Funding
- NIH [DA020830, CA197461]
- CIHR [FDN-154294, PJY-159710]
- Canada Research Chair
- Wellcome Trust
- European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007 [201413]
- NIAAA [AA-12502, AA-00145, AA-09203, AA15416, K02AA018755]
- Academy of Finland [100499, 205585, 118555, 141054, 264146, 308248, 312073, 288509, 312076, 285380, 312062, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071, 265240, 263278]
- Finnish Foundation for Cardiovascular Research
- Sigrid Juselius Foundation
- University of Helsinki HiLIFE Fellow grant
- Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility area of Kuopio
- Tampere and Turku University Hospitals [X51001]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Cultural Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- Yrjo Jahnsson Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation of Finnish Diabetes Association
- EU Horizon 2020 [755320]
- European Research Council [742927]
- Tampere University Hospital Supporting Foundation
- Doctoral Program in Population Health (University of Helsinki)
- Finnish Research Foundation of the Pulmonary Diseases
- Biomedicum Helsinki Foundation
- Cancer Foundation Finland
- Academy of Finland (AKA) [312062, 312076, 312062] Funding Source: Academy of Finland (AKA)
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This study conducted the largest GWAS to date on NMR in European ancestry current smokers, identifying multiple genetic variants associated with nicotine clearance rate. Understanding the genetic factors influencing smoking-related traits can facilitate epidemiological studies of smoking and disease, and optimize smoking cessation support to reduce the personal and societal costs associated with smoking.
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 similar to 38% of NMR variation, a substantial increase from the similar to 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.
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