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
17135278
TITLE
Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.
ABSTRACT
Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.
DATE PUBLISHED
2007 Jan 1
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2006/11/29
pubmed 2006/12/01 09:00
medline 2007/04/04 09:00
entrez 2006/12/01 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Saccone SF Saccone Scott F SF Department of Psychiatry, Box 8134, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA. saccones@msnotes.wustl.edu
Hinrichs AL Hinrichs Anthony L AL
Saccone NL Saccone Nancy L NL
Chase GA Chase Gary A GA
Konvicka K Konvicka Karel K
Madden PA Madden Pamela A F PA
Breslau N Breslau Naomi N
Johnson EO Johnson Eric O EO
Hatsukami D Hatsukami Dorothy D
Pomerleau O Pomerleau Ovide O
Swan GE Swan Gary E GE
Goate AM Goate Alison M AM
Rutter J Rutter Joni J
Bertelsen S Bertelsen Sarah S
Fox L Fox Louis L
Fugman D Fugman Douglas D
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Wang JC Wang Jen C JC
Ballinger DG Ballinger Dennis G DG
Rice JP Rice John P JP
Bierut LJ Bierut Laura Jean LJ
INVESTIGATORS
JOURNAL
VOLUME: 16
ISSUE: 1
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2007
MONTH: Jan
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Print
ISSN: 0964-6906
ISSNTYPE: Print
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
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GRANTS
GRANTID AGENCY COUNTRY
CA89392 NCI NIH HHS United States
DA015129 NIDA NIH HHS United States
DA12854 NIDA NIH HHS United States
N01DA-0-7079 NIDA NIH HHS United States
P01 CA089392 NCI NIH HHS United States
P01 CA089392-05 NCI NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Aged
Aged, 80 and over
Case-Control Studies
Chromosomes, Human, Pair 8
Cluster Analysis
Female
Genetic Markers genetics
Genetic Variation genetics
Genotype genetics
Humans genetics
Male genetics
Middle Aged genetics
Polymorphism, Single Nucleotide genetics
Receptors, Nicotinic genetics
Tobacco Use Disorder genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Genetic Markers
0 Receptors, Nicotinic
OTHER ID's
OTHERID SOURCE
NIHMS32504 NLM
PMC2270437 NLM
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Last Modified: Oct 15 2007