CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women.

Differences in drinking patterns and problems between different racial or ethnic groups highlight the importance of studying the etiology of alcohol involvement in Hispanics (Dawson, 1998; Grant et al., 2004; Nielsen, 2000). Mexican Americans are the largest subgroup of Hispanic Americans, with nearly two-thirds of the total U.S. Hispanic population. There is evidence to suggest that Mexican Americans are at higher risk for hazardous patterns of alcohol drinking (Ramisetty-Mikler et al., 2010), alcohol use disorders (AUD) (Caetano et al., 2008a), and alcohol-related accidents (Caetano et al., 2008b). Studies in first generation (immigrant generation) Mexican Americans have demonstrated that alcohol use and other psychiatric disorders increase in frequency with time spent in the U.S., and these disorders further increase in frequency in subsequent (U.S.-born) generations of Mexican Americans. For example, U.S.-born Mexican Americans have rates of alcohol use and psychiatric disorders that are 2 to 3 times higher than their Mexican-born ancestors (Burnam et al., 1987; Golding et al., 1990; Grant et al., 2004; Kessler et al., 1994; Strunin et al., 2007; Vega et al., 1998, 2003;). It has been hypothesized that this increase in prevalence rates is the result of a transgenerational process of adapting to living in the US (Burnam et al., 1987; Escobar, 1998; Ortega et al., 2000), thus suggesting that environmental factors may increase the susceptibility to psychiatric disorders in this population. Nonetheless, a recent family study of Mexican-Americans suggests that substantial genetic influences are also involved in the development of AUD in this population (Olvera et al., 2011). However, how genetic influences affect behavioral traits associated with the increased risk of AUDs in Mexican Americans is not well understood. The expression of certain personality traits is a prominent factor associated with an increase in the risk for alcohol dependence and substance abuse (see Acton, 2003; Cloninger et al., 1988; Larkins & Sher, 2006; Pihl & Peterson, 1995; Sher & Trull, 1994; Sher et al., 1999, 2000). Neuroticism is a personality trait that has been shown to influence the use and abuse of alcohol (see Larkins & Sher, 2006; Read & O’Connor, 2006; Sher & Trull, 1994). High levels of neuroticism have also been associated with cigarette smoking, marijuana use and polysubstance abuse (McCormick et al., 1998; Terracciano & Costa, 2004; Terracciano et al., 2008). There is considerable evidence that neuroticism is associated with an increased susceptibility to stressors in U.S.-born Mexican Americans (Finch et al., 2000; Mangold et al., 2007, 2012; Romero & Roberts, 2003). We have previously shown that Mexican American participants with a lifetime history of alcohol dependence exhibited an increase in neuroticism scores, compared to age-matched controls (Criado & Ehlers, 2007). While many studies have shown a relationship between AUD and neuroticism (e.g., Read & O’Connor, 2006; Sher et al., 2005), neuroticism may be a risk as well as a protective factor for alcohol use. Read & O’Connor (2006) suggested two distinct pathways leading from neuroticism to alcohol use. The first (direct) pathway defines neuroticism as a protective factor for alcohol use that biases attention toward the negative consequences of drinking, thus reducing use. The second (indirect) pathway defines neuroticism as a risk factor for alcohol use via increased positive expectancies regarding the effects of alcohol. Additional studies, however, have suggested a bidirectional relation between neuroticism and alcohol use demonstrating that increases in neuroticism can result from long-term alcohol use (Sutherland, 1997). These findings suggest a more complex association between neuroticism and AUD. Further, the relationship between personality traits and genetic markers associated with the increased risk for alcohol dependence in Mexican Americans is not well understood. The identification of genetic markers associated with neuroticism and their influence on the development of AUD and drug dependence in Mexican Americans may help in determining the relationship between basic molecular processes and clinical phenomena associated with the disorder in the broader general population. Neuronal nicotinic receptors (nAChRs) are important therapeutic targets for the treatment of AUDs (Chatterjee & Bartlett, 2010). Preclinical studies have shown evidence of a relationship between α5 and α3 nAChRs subunits and alcohol-seeking behaviors. A recent study found that pharmacological activation of α3β4 nAChRs selectively decreases ethanol, but not sucrose consumption, in animal models (Chatterjee et al., 2011). Moreover, studies in animal models have provided evidence that genetic variations of nAChR subunits, including the α5 and β4 nAChRs subunits, are associated with alcohol preference and consumption (see Tuesta et al., 2011). In humans, the genomic region on chromosome 15q25 encoding the α5 (CHRNA5) and α3 (CHRNA3) nAChR subunits has been associated with vulnerability to nicotine addiction with the strongest effects observed for a nonsynonymous SNP in exon 5 of CHRNA5 and a highly correlated synonymous SNP in exon 5 of CHRNA3 (e.g., Bierut et al., 2008; Saccone et al., 2009, 2010; Schlaepfer et al., 2008; Sherva et al., 2010; Tobacco and Genetics (TAG) Consortium, 2010; Wang et al., 2009b). Additional studies have reported evidence of association between these SNPs and alcohol consumption, level of response to alcohol, and alcohol dependence (e.g., Chen et al., 2009; Joslyn et al., 2008; Schlaepfer et al., 2008; Wang et al., 2009a). Associations independent of these SNPs may also be present in the region (e.g., Joslyn et al., 2008; Wang et al., 2009a) indicating that multiple variants in the chromosome 15 nicotinic receptor gene cluster may influence the development of AUD and related traits. The present report is part of a larger study exploring genetic risk factors for AUD among Mexican Americans (e.g., Ehlers & Phillips, 2007; Ehlers et al., 2012). Understanding the relationship between neuroticism and genetic markers associated with an increased risk for alcohol and drug dependence may provide critical information on risk and protective factors for addiction in Mexican American men and women. Thus, the primary aim of the study was to determine if significant associations could be detected between 13 SNPs in the CHRNA5 and CHRNA3 genes (rs684513, rs588765, rs601079, rs680244, rs692780, rs555018, rs16969968, rs1979906, LOC123688 rs8034191, rs578776, rs6495307, rs1051730 and rs3743078) and neuroticism in young adult Mexican American men and women. A secondary aim was to determine if significant associations could be detected between these SNPs and alcohol dependence, and if so, whether these observed associations were mediated by the presence of neuroticism. Although the primary focus of the present report was on the relations between the measured SNPs, neuroticism, and alcohol use, SNPs in CHRNA3 and CHRNA5 have shown strong relations with smoking behaviors as described. Thus, we also conducted a parallel set of mediation analyses between these SNPs, nicotine dependence, and neuroticism.