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Human Molecular Genetics Advance Access published online on December 7, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl441
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© The Author 2006. Published by Oxford University Press. All rights reserved

Novel Genes Identified in a High Density Genome Wide Association Study for Nicotine Dependence

Laura Jean Bierut1,*, Pamela A. F. Madden1, Naomi Breslau2, Eric O. Johnson3, Dorothy Hatsukami4, Ovide F. Pomerleau5, Gary E. Swan6, Joni Rutter7, Sarah Bertelsen1, Louis Fox1, Douglas Fugman8, Alison M. Goate1, Anthony L. Hinrichs1, Karel Konvicka9, Nicholas G. Martin10, Grant W. Montgomery10, Nancy L. Saccone1, Scott F. Saccone1, Jen C. Wang1, Gary A. Chase11, John P. Rice1 and Dennis G. Ballinger9

1 Washington University School of Medicine, St. Louis, MO, USA 2 Michigan State University, East Lansing, MI, USA 3 Research Triangle Institute International, Research Triangle Park, NC, USA 4 University of Minnesota, Minneapolis, MN, USA 5 University of Michigan, Ann Arbor, MI, USA 6 SRI International, Menlo Park, CA, USA 7 National Institute on Drug Abuse, Rockville, MD, USA 8 Rutgers University, Piscataway, NJ, USA 9 Perlegen Sciences, Mountain View, CA, USA 10 Queensland Institute of Medical Research, Herston QLD, Australia 11 Penn State College of Medicine, Hershey, PA, USA

* Please address correspondence to: Laura Jean Bierut, M.D., 660 South Euclid, Washington University School of Medicine, Department of Psychiatry, Box 8134, St. Louis, MO 63110, Phone: (314) 362-3492, Fax: (314) 362-4247, E-mail: bierutl{at}msnotes.wustl.edu

Received August 11, 2006; Revised November 15, 2006; Accepted November 15, 2006

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 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 1.53x10–6). 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 ß3 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.


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