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| PMID |
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| TITLE |
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| Genome-wide association meta-analysis of nicotine metabolism and cigarette consumption measures in smokers of European descent. |
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| ABSTRACT |
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| 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. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2019/05/03 |
| accepted |
2020/02/21 |
| revised |
2020/02/18 |
| entrez |
2020/03/12 06:00 |
| pubmed |
2020/03/12 06:00 |
| medline |
2020/03/12 06:00 |
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| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Buchwald J |
|
Buchwald |
Jadwiga |
J |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Chenoweth MJ |
|
Chenoweth |
Meghan J |
MJ |
|
Campbell Family Mental Health Research Institute, CAMH, and Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. |
| Palviainen T |
|
Palviainen |
Teemu |
T |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Zhu G |
|
Zhu |
Gu |
G |
|
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Benner C |
|
Benner |
Christian |
C |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Gordon S |
|
Gordon |
Scott |
S |
|
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Korhonen T |
|
Korhonen |
Tellervo |
T |
|
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. |
| Ripatti S |
|
Ripatti |
Samuli |
S |
|
Broad Institute of MIT and Harvard, Cambridge, MA, USA. |
| Madden PAF |
|
Madden |
Pamela A F |
PAF |
|
Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA. |
| Lehtimäki T |
|
Lehtimäki |
Terho |
T |
|
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. |
| Raitakari OT |
|
Raitakari |
Olli T |
OT |
|
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. |
| Salomaa V |
|
Salomaa |
Veikko |
V |
|
Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. |
| Rose RJ |
|
Rose |
Richard J |
RJ |
|
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. |
| George TP |
|
George |
Tony P |
TP |
|
Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada. |
| Lerman C |
|
Lerman |
Caryn |
C |
|
USC Norris Comprehensive Cancer Center at Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. |
| Pirinen M |
|
Pirinen |
Matti |
M |
|
Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Kaprio J |
|
Kaprio |
Jaakko |
J |
|
Department of Public Health, University of Helsinki, Helsinki, Finland. |
| Loukola A |
|
Loukola |
Anu |
A |
|
Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland. |
| Tyndale RF |
|
Tyndale |
Rachel F |
RF |
|
Department of Psychiatry, University of Toronto, Toronto, ON, Canada. r.tyndale@utoronto.ca. |
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| INVESTIGATORS |
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| JOURNAL |
|
| VOLUME: |
| ISSUE: |
| TITLE: Molecular psychiatry |
| ISOABBREVIATION: Mol. Psychiatry |
| YEAR: 2020 |
| MONTH: Mar |
| DAY: 10 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1476-5578 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
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| MEDLINETA: Mol Psychiatry |
| COUNTRY: England |
| ISSNLINKING: 1359-4184 |
| NLMUNIQUEID: 9607835 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| 100499, 205585, 118555, 141054, 264146, 308248, and 312073 |
Academy of Finland (Suomen Akatemia) |
|
| 288509 and 312076 |
Academy of Finland (Suomen Akatemia) |
|
| AA-00145, AA-12502, AA-09203 |
U.S. Department of Health & Human Services | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAAA) |
|
| DA020830 |
U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) |
|
| CA197461 |
U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) |
|
| 285380 and 312062 |
Academy of Finland (Suomen Akatemia) |
|
| U01 DA020830 |
NIDA NIH HHS |
United States |
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