Linkage scan of nicotine dependence in the University of California, San Francisco (UCSF) Family Alcoholism Study

Tobacco-related illnesses have been estimated to claim 435,000 lives annually, thus constituting a serious and costly public health issue (Mokdad et al., 2004). Twin studies suggest a substantial genetic component to the development of nicotine dependence (e.g., Carmelli et al., 1990; Kendler et al., 1999; True et al., 1999),and a recent meta-analysis reported heritability estimates for smoking initiation ranging from 37–55% and persistent smoking ranging from 46–59% (Li et al., 2003). Given such evidence several genome-wide linkage analyses have been conducted for a variety of tobacco-related phenotypes (e.g., DSM-IV nicotine dependence [American Psychiatric Association, 1994], smoking quantity, and the Fagerstrom Nicotine Dependence Scale [Heatherton et al., 1991]) to identify susceptibility loci related to nicotine dependence (Li, 2008). The earliest studies were conducted using an extended family design in the Collaborative Studies on the Genetics of Alcoholism (COGA) sample (Duggirala et al., 1999) and a sib-pair design in samples collected in Christchurch, New Zealand and Richmond, Virginia USA (Straub et al., 1999). Following these initial studies, more than 20 genome-wide linkage scans of tobacco-related phenotypes have been published, and several susceptibility regions have been identified across studies, including regions on chromosomes 9, 10, 11, and 17 (Li, 2008). Association studies have begun to identify specific genes that underlie these linkage regions. For example, three independent studies have reported evidence of linkage between nicotine-related phenotypes and a region of chromosome 17 (20–65 cM) (Duggirala et al., 1999; Li et al., 2008; Wang et al., 2005). A recent candidate gene study suggested polymorphisms in the nicotinic acetylcholine beta 1 receptor subtype gene (CHRNB1) may be responsible for this linkage signal (Lou et al., 2006). Additionally, studies conducted using the COGA sample have reported evidence of linkage between nicotine-related phenotypes and chromosome 2 at 85 cM (Bergen et al., 1999; Bierut et al., 2004). This region includes the neurexin 1 gene (NRXN1), which contains polymorphisms associated with nicotine dependence in a recent genome-wide association study (GWAS) (Bierut et al., 2007) as well as recent candidate gene studies (Nussbaum et al., 2008; Sherva et al., 2008). These studies demonstrate the progress being made in understanding the genetic contributions to tobacco-related phenotypes and how linkage analysis has aided in the identification of susceptibility loci for such traits. In addition to identifying susceptibility loci for nicotine dependence specifically, several studies have tried to identify loci that contribute to substance dependence more generally by searching for genomic regions that confer risk to both nicotine and alcohol dependence. Such studies are justified by twin studies indicating a shared genetic etiology between these two disorders (Swan et al., 1997; True et al., 1999), and several have reported positive findings. For example, data from the COGA sample suggest that the susceptibility locus on chromosome 2 containing NRXN1 contributed to both nicotine and alcohol dependence (Bergen et al., 1999). Further, a study of the Mission Indian population found that the chromosome 4 region containing the alcohol dehydrogenase gene cluster contributed to increased risk for both disorders (Ehlers and Wilhelmsen, 2006). In addition, a Finnish twin sample was used to identify loci on chromosomes 7 and 11 (Loukola et al., 2008) and sibling pairs collected in Ireland were used to identify loci on chromosomes 7 and 18 (Sullivan et al., 2008) conferring risk for both disorders. Such studies provide important insights into how different chromosomal regions confer risk to substance dependence whether it is towards a specific substance or towards a more general tendency toward addictive behavior. The current study conducted a genome-wide linkage scan for nicotine dependence in the UCSF Family Alcoholism Study to support and extend previous findings. Linkage peaks were followed-up by analyzing each of the 14 nicotine dependence symptoms assessed by the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) (Bucholz et al., 1994) to identify those symptoms responsible for the reported linkage signals. A further aim was to determine whether the linked genomic regions contributed to nicotine dependence specifically, or whether they might confer increased risk to addiction more generally by showing evidence of linkage to both alcohol and nicotine dependence. Thus, supplementary genome-wide linkage scans of nicotine dependence were conducted utilizing alcohol dependence diagnoses alternatively as a covariate and as an additional predictor in a bivariate analysis.