Association Study of CHRM2 Polymorphisms with Substance-Use Pathology and Personality Traits

Abstract

A growing literature exists on the association of CHRM2 (the gene coding for cholinergic muscarinic receptor 2) with alcohol dependence (Wang et al., 2004), with the broader phenotype of substance dependence in general (Luo et al., 2005; Dick, Agrawal, et al., 2007), and with the still-broader phenotype of externalizing psychopathology (Dick et al., 2008). Additionally, one study has found association between CHRM2 and the personality traits of Agreeableness and Conscientiousness; its authors suggest that personality may substantially mediate the heritability of substance dependence (Luo et al., 2007). Guided by the relevant literature, which is reviewed at length, the present study investigates: (1) the association of CHRM2 and risk of substance use disorders; (2) the association of CHRM2 with personality characteristics; and, conditional on replication of these main effects, (3) the extent to which personality mediates CHRM2’s influence on substance use disorders. We use data from genotyped participants in two longitudinal studies, one of twins and their families and one of adopted siblings and their families. We use Raw Maximum Likelihood in Mx (see Neale et al., 2003) to examine the association of 4 CHRM2 SNPs with personality traits and with composite measures of disordered substance use, while taking into account the phenotypic covariance in different types of families. Our results provide no clear evidence of association of CHRM2 polymorphisms with broad personality traits or substance-abuse pathology. However, the validity of our results is considerably limited by the non-multivariate-normal distribution of the substance-use pathology variable, incompleteness of the available data, use of self-reported ethnicity instead of genomically-determined ancestry, and sparse coverage of the CHRM2 gene.