Funding National Institute for Health and Clinical Excellence Th

Funding National Institute for Health and Clinical Excellence. The views expressed are those of the authors and not necessarily those of the institute. National Institute of Health Research Career reference Scientist Award to PA. Declaration of Interests PA has accepted money from Pfizer, McNeil AB, and Xenova for advice about smoking cessation paid to his institution and him personally. The payments from McNeil AB, the company that sponsored the NARS trials described here, were unrelated to the NARS trials or the work described here. No other authors have competing interests to declare. Supplementary Material [Article Summary] Click here to view. Acknowledgments The authors thank Jon Deeks for his valuable statistical advice.

Approximately 27% of Americans use nicotine regularly, with approximately 24% meeting Diagnostics and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for nicotine dependence at some point in their lives (Breslau, Johnson, Hiripi, & Kessler, 2001). Decades of twin and family studies have demonstrated consistently that approximately 50% of total vulnerability to nicotine dependence results from heritable factors (True et al., 1999; Tsuang, Bar, Harley, & Lyons, 2001). Since smoking results in 400,000 deaths and $157 billion in economic expenditures annually in the United States, the identification of the genetic architecture that initiates and maintains nicotine dependence is a high public health priority (Centers for Disease Control and Prevention, 2002).

In response to this challenge, a large number of genetic studies have attempted to identify gene loci containing variability that affects vulnerability to nicotine dependence. Before 2005, these reports consisted largely of candidate gene and linkage analyses (Li, 2006). Many of these studies were pivotal in advancing our understanding of the role of genetic variation in critical gene pathways, such as the cholinergic neurotransmission system, in altering vulnerability to nicotine dependence. However, these linkage and candidate gene studies were limited by either sample size or scale of genotyping. In an attempt to transcend these problems, the National Institute on Drug Abuse funded a pair of large-scale association studies by a group of investigators in collaboration with Perlegen Sciences (Mountain View, CA) referred to as the Collaborative Study of the Genetics of Nicotine Dependence (NICSNP) consortium.

This consortium first performed a high-density association case�Ccontrol analysis of 482 nicotine dependence Cilengitide cases and 466 controls using a 2.4 million single nucleotide polymorphism (SNP) platform and a DNA pooling technique (Bierut et al., 2007). This was then followed by individual genotyping of the 39,213 SNPs showing the strongest evidence of association in a sample of 1,050 cases and 879 controls.

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