@article{8c9dbadc472b4d4c80d9442ee1d65d2c,
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 Fagerstr{\"o}m 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 Fagerstr{\"o}m 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.",
keywords = "AMPK pathway, DISC1, DLC1, FTND, GWAS, Nicotine dependence, Population differences, eNOS pathway",
author = "Joel Gelernter and Kranzler, {Henry R.} and Richard Sherva and Laura Almasy and Herman, {Aryeh I.} and Ryan Koesterer and Hongyu Zhao and Farrer, {Lindsay A.}",
note = "Funding Information: Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism ( U10 AA008401 ), the Collaborative Genetic Study of Nicotine Dependence ( P01 CA089392 ), and the Family Study of Cocaine Dependence ( R01 DA013423 ). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the National Institutes of Health Genes, Environment and Health Initiative ( U01HG004438 ); the National Institute on Alcohol Abuse and Alcoholism; the National Institute on Drug Abuse; and the National Institutes of Health contract “High throughput genotyping for studying the genetic contributions to human disease” ( HHSN268200782096C ). Funding Information: We appreciate the work in recruitment and assessment provided at Yale University School of Medicine and the APT Foundation by James Poling, Ph.D.; at McLean Hospital by Roger Weiss, M.D.; at the Medical University of South Carolina by Kathleen Brady, M.D., Ph.D., and Raymond Anton, M.D.; and at the University of Pennsylvania by David Oslin, M.D. Genotyping services for a part of our genome-wide association study were provided by the Center for Inherited Disease Research and Yale University (Center for Genome Analysis). Center for Inherited Disease Research is fully funded through a Federal contract from the National Institutes of Health to The Johns Hopkins University (contract number N01-HG-65403). We are grateful to Ann Marie Lacobelle, Catherine Aldi, and Christa Robinson for their excellent technical assistance; to the Semi-structured Assessment for Drug Dependence and Alcoholism interviewers, led by Yari Nu{\~n}ez and Michelle Slivinsky, who devoted substantial time and effort to phenotype the study sample; and to John Farrell and Alexan Mardigan for database management assistance. Funding Information: The publicly available datasets used for the analyses described in this manuscript were obtained from the dbGAP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000092.v1.p1 through dbGAP accession number phs000092.v1.p. Funding support for the Study of Addiction: Genetics and Environment was provided through the National Institutes of Health Genes, Environment and Health Initiative ( U01 HG004422 ). Study of Addiction: Genetics and Environment is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under the Genes, Environment and Health Initiative. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies Coordinating Center ( U01 HG004446 ). Funding Information: This study was supported by National Institutes of Health Grants RC2 DA028909 , R01 DA12690 , R01 DA12849 , R01 DA18432 , R01 AA11330 , and R01 AA017535 and the Veterans Affairs Connecticut and Philadelphia Veterans Affairs Mental Illness Research, Educational, and Clinical Centers. Publisher Copyright: {\textcopyright} 2015 Society of Biological Psychiatry.",
year = "2015",
month = mar,
day = "1",
doi = "10.1016/j.biopsych.2014.08.025",
language = "English (US)",
volume = "77",
pages = "493--503",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "5",
}