Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22451501
TITLE
Use of a predictive model derived from in vivo endophenotype measurements to demonstrate associations with a complex locus, CYP2A6.
ABSTRACT
This study demonstrates a novel approach to test associations between highly heterogeneous genetic loci and complex phenotypes. Previous investigations of the relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes made comparisons by dividing subjects into broad categories based on assumptions that simplify the range of function of different CYP2A6 alleles, their numerous possible diplotype combinations and non-additive allele effects. A predictive model that translates CYP2A6 diplotype into a single continuous variable was previously derived from an in vivo metabolism experiment in 189 European Americans. Here, we apply this model to assess associations between genotype, inferred nicotine metabolism and smoking behaviors in larger samples without direct nicotine metabolism measurements. CYP2A6 genotype is not associated with nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence, demonstrating that cigarettes smoked per day (CPD) and nicotine dependence have distinct genetic correlates. The predicted metric is significantly associated with CPD among African Americans and European American dependent smokers. Individual slow metabolizing genotypes are associated with lower CPD, but the predicted metric is the best predictor of CPD. Furthermore, optimizing the predictive model by including additional CYP2A6 alleles improves the fit of the model in an independent data set and provides a novel method of predicting the functional impact of alleles without direct metabolism measurements. Lastly, comprehensive genotyping and in vivo metabolism data are used to demonstrate that genome-wide significant associations between CPD and single nucleotide polymorphisms are the result of synthetic associations.
DATE PUBLISHED
2012 Jul 1
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2012/03/26
aheadofprint 2012/04/06
entrez 2012/03/28 06:00
pubmed 2012/03/28 06:00
medline 2012/12/14 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Bloom AJ Bloom A Joseph AJ Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, Saint Louis, MO 63119, USA. bloomj@psychiatry.wustl.edu
Harari O Harari Oscar O
Martinez M Martinez Maribel M
Madden PA Madden Pamela A F PA
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Rice JP Rice John P JP
Murphy SE Murphy Sharon E SE
Bierut LJ Bierut Laura J LJ
Goate A Goate Alison A
INVESTIGATORS
JOURNAL
VOLUME: 21
ISSUE: 13
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2012
MONTH: Jul
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2083
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
Cites Drug Alcohol Depend. 2007 Jan 12;86(2-3):294-300 16930853
Cites Pharmacogenet Genomics. 2011 Jul;21(7):403-16 21597399
Cites Hum Mol Genet. 2007 Jan 1;16(1):36-49 17135278
Cites Hum Mol Genet. 2007 Jan 1;16(1):24-35 17158188
Cites Drug Metab Dispos. 2007 Apr;35(4):515-20 17267622
Cites Am J Hum Genet. 2007 May;80(5):856-66 17436240
Cites Pharmacol Biochem Behav. 2000 Jul;66(3):553-8 10899369
Cites Drug Metab Dispos. 2001 Apr;29(4 Pt 2):548-52 11259349
Cites Nicotine Tob Res. 2003 Oct;5(5):621-4 14577978
Cites J Natl Cancer Inst. 2004 Jun 2;96(11):844-52 15173268
Cites Pharmacogenetics. 2004 Jun;14(6):369-79 15247629
Cites Pharmacogenetics. 2004 Sep;14(9):615-26 15475735
Cites Biochemistry. 1990 Feb 6;29(5):1322-9 2322567
Cites J Consult Clin Psychol. 1993 Oct;61(5):723-31 8245270
Cites Tob Control. 2004 Dec;13(4):422-8 15564629
Cites Bioinformatics. 2005 Jan 15;21(2):263-5 15297300
Cites Clin Pharmacol Ther. 2005 Mar;77(3):145-58 15735609
Cites Pharmacol Rev. 2005 Mar;57(1):79-115 15734728
Cites Pharmacogenet Genomics. 2005 Sep;15(9):609-24 16041240
Cites Biochem Pharmacol. 2005 Sep 1;70(5):801-8 15993850
Cites Mol Psychiatry. 2006 Apr;11(4):400-9 16402128
Cites Pharmacogenet Genomics. 2008 Jan;18(1):67-75 18216723
Cites Hum Mutat. 2008 May;29(5):679-88 18360915
Cites Nat Biotechnol. 2008 Aug;26(8):897-9 18688245
Cites Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):453-66 19259974
Cites Cancer Res. 2009 Sep 1;69(17):6848-56 19706762
Cites Theor Popul Biol. 2010 Feb;77(1):1-5 19818800
Cites PLoS Biol. 2010 Jan;8(1):e1000294 20126254
Cites Eur J Clin Pharmacol. 2010 Mar;66(3):239-51 20012030
Cites Nat Genet. 2010 May;42(5):448-53 20418888
Cites Nat Genet. 2010 May;42(5):441-7 20418890
Cites PLoS Biol. 2011;9(1):e1001008 21267066
Cites Addiction. 2011 May;106(5):985-94 21205058
Cites Pediatrics. 2007 Jan;119(1):e264-74 17130279
GRANTS
GRANTID AGENCY COUNTRY
CA089392 NCI NIH HHS United States
CA77598 NCI NIH HHS United States
DA021237 NIDA NIH HHS United States
DA025888 NIDA NIH HHS United States
DA027995 NIDA NIH HHS United States
DA12854 NIDA NIH HHS United States
K02 DA021237 NIDA NIH HHS United States
P01 CA089392 NCI NIH HHS United States
R01 DA025888 NIDA NIH HHS United States
R25 DA027995 NIDA NIH HHS United States
T32 MH014677-32 NIMH NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
African Americans genetics
Alleles genetics
Aryl Hydrocarbon Hydroxylases genetics
Cytochrome P-450 CYP2A6 genetics
Endophenotypes genetics
European Continental Ancestry Group genetics
Gene Frequency genetics
Genetic Association Studies genetics
Genetic Variation genetics
Genotype genetics
Humans genetics
Nicotine metabolism
Phenotype metabolism
Polymorphism, Single Nucleotide metabolism
Smoking metabolism
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 CYP2A6 protein, human
6M3C89ZY6R Nicotine
EC 1.14.13.- Cytochrome P-450 CYP2A6
EC 1.14.14.1 Aryl Hydrocarbon Hydroxylases
OTHER ID's
OTHERID SOURCE
PMC3373237 NLM