title: Genome-wide association study of nicotine dependence in American populations: identification of novel risk loci in both African-Americans and European-Americans.
abstract: BACKGROUND
  We report a genome-wide association study (GWAS) of nicotine dependence defined on the basis of scores on the Fagerström Test for Nicotine Dependence in European-American (EA) and African-American (AA) populations.
  
  
  METHODS
  Our sample, from the one used in our previous GWAS, included only subjects who had smoked >100 cigarettes lifetime (2114 EA and 2602 AA subjects) and an additional 927 AA and 2003 EA subjects from the Study of Addiction: Genetics and Environment project [via the database of Genotypes and Phenotypes (dbGAP)]. GWAS analysis considered Fagerström Test for Nicotine Dependence score as an ordinal trait, separately in each population and sample and by combining the results in meta-analysis. We also conducted analyses that were adjusted for other substance use disorder criteria in a single nucleotide polymorphism (SNP) subset.
  
  
  RESULTS
  In EAs, one chromosome 7 intergenic region was genome-wide significant (GWS): rs13225753, p = 3.48 × 10(-8) (adjusted). In AAs, GWS associations were observed at numerous SNPs mapped to a region on chromosome 14 of >305,000 base pairs (minimal p = 4.74 × 10(-10)). Two chromosome 8 regions were associated: p = 4.45 × 10(-8) at DLC1 SNP rs289519 (unadjusted) and p = 1.10 × 10(-9) at rs6996964 (adjusted for other substances), located between CSGALNACT1 and INTS10. No GWS associations were observed at the chromosome 15 nicotinic receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) previously associated with nicotine dependence and smoking quantity traits. TSNAX-DISC1 SNP rs821722 (p = 1.46 × 10(-7)) was the most significant result with substantial contributions from both populations; we previously identified DISC1 associations with opioid dependence. Pathway analysis identified association with nitric oxide synthase and adenosine monophosphate-activated protein kinase pathways in EAs.
  
  
  CONCLUSIONS
  The key risk loci identified, which require replication, offer novel insights into nicotine dependence biology.
authors.affiliation: Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven; Departments of Genetics and Neurobiology, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut. Electronic address: joel.gelernter@yale.edu.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Psychiatry, Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, and Veterans Integrated Service Network 4 Mental Illness Research, Educational, and. Clinical Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Department of Psychiatry, Division of Human Genetics, Yale University School of Medicine, New Haven; Departments of Genetics and Neurobiology, Veterans Affairs Connecticut Healthcare Center, West Haven, Connecticut.
authors.forename: Aryeh I
authors.initials: AI
authors.lastname: Herman
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Ryan
authors.initials: R
authors.lastname: Koesterer
authors.affiliation: Departments Biostatistics and Genetics, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts; Departments of Neurology, Ophthalmology, Genetics and Genomics, and Epidemiology and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
mesh_terms: D001741:Black or African American / Q000235:genetics*; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D012907:Smoking / Q000235:genetics; D014029:Tobacco Use Disorder / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics*
keywords: AMPK pathway; DISC1; DLC1; FTND; GWAS; Nicotine dependence; Population differences; eNOS pathway