title: Novel genes identified in a high-density genome wide association study for nicotine dependence.
abstract: Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 South Euclid, Box 8134, St Louis, MO 63110, USA. bierut@msnotes.wustl.edu
authors.forename: Laura Jean
authors.initials: LJ
authors.lastname: Bierut
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Naomi
authors.initials: N
authors.lastname: Breslau
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.forename: Ovide F
authors.initials: OF
authors.lastname: Pomerleau
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Joni
authors.initials: J
authors.lastname: Rutter
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.forename: Louis
authors.initials: L
authors.lastname: Fox
authors.forename: Douglas
authors.initials: D
authors.lastname: Fugman
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Hinrichs
authors.forename: Karel
authors.initials: K
authors.lastname: Konvicka
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.forename: Scott F
authors.initials: SF
authors.lastname: Saccone
authors.forename: Jen C
authors.initials: JC
authors.lastname: Wang
authors.forename: Gary A
authors.initials: GA
authors.lastname: Chase
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Ballinger
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*