Personality Traits of Agreeableness and Extraversion are Associated with ADH4 Variation

According to the five-factor model of personality (Digman 1990), the full range of personality traits can be well defined in terms of five basic dimensions. These dimensions are: factor I (extraversion or surgency), which contrasts such traits as talkativeness, assertiveness, and activity level with silence, passivity, and reserve; factor II (agreeableness or pleasantness), which contrasts kindness, trust, and warmth with hostility, selfishness, and distrust; factor III (conscientiousness or dependability), which contrasts organization, thoroughness, and reliability with carelessness, negligence, and unreliability; factor IV (neuroticism versus emotional stability), which includes nervousness, moodiness, and temperamentality; and factor V (openness to experience or intellect), which contrasts imagination, curiosity, and creativity with shallowness and imperceptiveness (Goldberg 1993). This structure of traits in the five-factor model is consistent among highly diverse cultures with distinct languages and between men and women, older and younger adults, and European Americans (EAs) and non-European Americans (Costa et al 1991; McCrae and Costa 1997). This universality could reflect a common biological basis of personality traits across distinct cultures, populations, ages, and sexes. Based on its wide applicability and consistency, the five-factor model has been widely accepted. Genetic factors have been implicated as contributing to individual difference in major dimensions of personality traits, evidenced by a linkage study and many association studies. A genomewide-scan linkage study mapped five trait-influencing sites for neuroticism at chromosomes 1q, 4q, 7p, 12q, and 13q (Fullerton et al 2003). Subjects expressing one or both S alleles of a regulatory region polymorphism at the serotonin transporter gene (SLC6A4) tended to score lower on the NEO Five-Factor Inventory factor of agreeableness than subjects homozygous for the L allele; within this factor, the facet subscale of tendermindedness was lower for subjects expressing one or both S alleles compared with subjects homozygous for the L allele (p = .003) (Wand et al 2002). There have also been reports of an association between this polymorphism and harm avoidance (Wiesbeck et al 2004), neuroticism (Du et al 2000; Lesch et al 1996), violent behavior (Retz et al 2004), or other anxiety-related personality traits (Melke et al 2001). Many other studies have also reported on the relationship of personality traits with other candidate loci, such as variation at the 5-HT2C gene (Ebstein et al 1997), the 5-HT2A gene (Golimbet et al 2002), the DRD2 gene (Jonsson et al 2003; Lee et al 2003; Ponce et al 2003; Rosmond et al 2001), the DRD3 gene (Thome et al 1999), the DRD4 gene (Bau et al 1999; Gelernter et al 1997; Lee et al 2003), the COMT gene (Rujescu et al 2003; Tsai et al 2004), the BDNF gene (Itoh et al 2004; Lang et al 2004, 2005; Sen et al 2003), the OPRM1 gene (Wand et al 2002), the TFAP2B gene (Damberg et al 2000), and the ESR1 gene (Westberg et al 2003). These findings provide additional support for the hypothesis that personality traits are influenced by genetic factors. Personality traits may play a central role in the development of substance dependence (SD; including alcohol dependence and opioid dependence in the studies by Caspi et al 1997; Cloninger 1987; Cloninger et al 1988; Loper et al 1973; Verheul et al 2004; Zucker and Lisansky Gomberg 1986). Specifically, some premorbid personality traits, such as “behavioral under-control” (including impulsivity, thrill seeking, rebelliousness, irresponsibility, nonconformity, and aggressiveness) (Sher et al 1991), rejection of societal values, antisocial behavior, and hyperactivity, are robust predictors of alcohol dependence (Cox et al 1983; Otter and Martin 1996). In contrast, it has been argued that personality traits, especially “negative emotionality” (anxiousness, inhibition, moodiness, and unhappiness), may be a consequence rather than a cause of alcohol dependence (Schuckit 1986). Common genetic factors may largely underlie the association between personality traits and alcohol dependence. For example, in a community sample of 2682 twins, Slutske et al (1998) found that 70% of the association between antisociality and alcohol dependence was explained by common genetic factors; this study also showed that alcohol dependence and conduct disorder shared many personality traits (also confirmed by Krueger et al 2000; Sher and Trull 1994) that could be accounted for by common genetic risk factors. In a follow-up study, these authors confirmed the finding that these personality dimensions shared genetic risk factors with alcohol dependence (Slutske et al 2002). Studies of the offspring of alcoholics suggested that behavioral undercontrol might be related to the familial diathesis underlying alcohol dependence risk (e.g., Finn et al 2000; Sher et al 1991, 1999). There is also direct evidence that personality traits and alcohol dependence are linked to polymorphisms in the serotonin transporter gene (SLC6A4) and the μ-opioid receptor gene (OPRM1) (Sander et al 1998a, 1998b). These findings support the idea of a shared genetic basis for personality features and alcohol dependence. The development of alcohol dependence depends on heavy ethanol consumption, which appears to be influenced by alcohol dehydrogenase (ADH) activity. Increased ADH activity can increase the rate of alcohol metabolism, thereby increasing the production of the toxin acetaldehyde. If acetaldehyde is not metabolized quickly, it accumulates, resulting in an aversive “flushing reaction,” which can limit alcohol consumption and, hypothetically, thereby reduce the risk for alcohol dependence (Hasin et al 2002; Muramatsu et al 1995; Thomasson et al 1994). Conversely, decreased ADH activity may increase the risk for alcohol dependence (Hasin et al 2002; Thomasson et al 1994). Human ADH4 enzyme mainly contributes to liver ADH activity, and at intoxicating levels of alcohol, it may account for as much as 40% of the total ethanol oxidation rate (Ditlow et al 1984). A polymorphism mapped to the promoter region of the ADH4 locus at 4q22 (e.g., single nucleotide polymorphism [SNP]6: −75A/C [rs1800759]) could modulate ADH activity (Edenberg et al 1999). Guindalini et al (2005) reported that promoter variants, including −75A/C and −159A/G, were significantly associated with alcohol dependence in European Brazilians and African Brazilians. We (Luo et al 2006a) found that seven ADH4 markers (including −75A/C) were in strong linkage disequilibrium (LD) to form a haplotype block in EA and African American (AA) substance dependent subjects and healthy control subjects. The genotype frequency distributions of the seven ADH4 markers were in Hardy-Weinberg Disequilibrium (HWD) in the EA patients with SD but were in Hardy-Weinberg Equilibrium (HWE) in the EA healthy control subjects and the AA cases and control subjects. The genotypes of seven ADH4 markers were significantly associated with alcohol and/or drug dependence in EAs. Among these markers in EAs, SNP6 and SNP2 (rs1042364) were most significant HWD in cases with alcohol dependence and drug dependence, respectively; also, these two markers were most significantly associated with alcohol dependence and drug dependence, respectively. Fine mapping the risk loci with an HWD measure (Feder et al 1996) revealed that these two markers were closest to the risk loci for alcohol dependence and drug dependence, respectively. After correcting for the effects of allele frequencies of markers on HWD (Jiang et al 2001), SNP6 was the marker closest to the risk loci for both alcohol dependence and drug dependence. We hypothesized that personality traits would also be associated with ADH4 variation, due to their strong genetic link to SD and the strong association between SD and ADH4. The present study aimed to investigate the role of these seven ADH4 markers in determining differences in personality traits among individuals.