The present study provides strong evidence that personality traits are related to ADH4 variation. Several ADH4 markers contribute to variation in personality traits, among which the functional variant SNP6 (rs1800759) in the promoter region is the most important, as predicted. Using MANCOVA and the Roy-Bargmann stepdown ANCOVA analyses, we were able to correlate personality factors, the interactions among markers, and the interactions between markers and covariates, while controlling for potential biases. In these two analyses, subjects that differed on affection status, age, population, and sex were combined in a single model, thus maximizing the statistical power of the analysis. Use of MANCOVA made it possible to examine diplotypes, which incorporate the LD information between markers, in addition to the information from all single markers and unknown markers and thus are likely to be more representative of a “whole gene” than any single marker. Our use of quantitative, rather than categorical, phenotypic information is also an important advantage of this analytic approach.
Diplotypewise analysis showed that the personality factors were associated with the diplotypes TTACAAA/TCACTAG and TTACAAA/CCGATCG (which harbor the allele A or genotype A/A of SNP6; associations were modified by diagnosis, sex, age, or ancestry), suggesting that ADH4 harbors risk loci for the variation observed in the personality traits. Allelewise and genotypewise MANCOVAs, which in decomposing the findings from diplotypewise analysis also provided support for those analyses, demonstrated that the personality factors were related to diagnosis, age, and ancestry and that the marker SNP6 was the most important genetic variant affecting the personality factors.
The Roy-Bargmann stepdown ANCOVAs, which were used to decompose the overall personality traits to identify more specific sources of association, sometimes were more powerful than MANCOVAs. This is evidenced by the facts that at this step in the analysis: 1) in the genotypewise analyses, the associations between covariates and personality factors became more significant ( versus ); and 2) markers (i.e., SNPs 1 and 2), in addition to SNP6, were found to be associated with personality traits. This analysis also demonstrated that a personality factor (i.e., extraversion) was affected by two ADH4 markers (i.e., SNPs1 and 2), although these associations were modified by another specific personality factor (i.e., conscientiousness), which may be because of the strong correlation (p = 1.2 × 10−15) between these two personality factors.
We also decomposed every risk covariate and marker revealed by the Roy-Bargmann stepdown analysis to identify the sources of association (i.e., specific risk covariates, risk alleles, and risk genotypes), using t
test, one-way ANOVA, and post hoc tests (). However, because the interaction effects between markers and covariates and between markers were ignored in these analyses, the effects of markers became less significant or nonsignificant ( versus ), which is consistent with the conclusion by Marchini et al (2005)
that interaction analysis is more powerful than noninteraction analysis. In view of this point and other issues described above, our conclusions should be drawn primarily from the Roy-Bargmann stepdown analyses, the findings from which show very high levels of statistical significance (1.2 × 10−43
≤ .009; ), although some findings from decomposing analyses become considerably less strong or nonsignificant ().
Our analyses demonstrated that of the markers studied, SNP6 had the most significant effect on personality traits. This is a functional variant at the promoter that leads to an alteration of ADH4
promoter activity, significantly affecting the expression of π ADH; the A allele has promoter activity more than twice that of the C allele (Edenberg et al 1999
). This variant has been reported to be associated with risk for alcohol dependence in European Brazilians and African Brazilians (Guindalini et al 2005
). We (Luo et al 2006a
) have reported that this variant was also strongly associated with SD and was the marker closest to the putative disease locus for SD; its minor A/A genotype increases risk for SD, that is, this is an SD-risk variant. In the present study, we observed that minor allele A increased the agreeableness score in male subjects (especially in older individuals), and allele A genotype A/A decreased the agreeableness score in female subjects (especially in younger individuals). This does not conflict in the sense that agreeableness scores in older male subjects and younger female subjects are very similar to one another; both groups of subjects have scores around 30.8 ± 5.9. The moderating effect of age on this marker between male subjects and female subjects indicates that the gene effect on personality traits is modified by sex and age, which is consistent with the extant literature on the topic. First, associations between personality traits and SD have been shown to be modified by sex. For example, the “positive emotionality” (outgoing, lively, persistent, and warm; measured by Tridimensional Personality Questionnaire [TPQ] and Eysenck Personality Questionnaire-Revised [EPQ-R]) may be more strongly associated with alcohol dependence among women than among men (Slutske et al 2002
); “negative emotionality” accounts for a portion of the genetic risk for alcohol dependence among men but not among women; and “behavioral undercontrol” accounts for significantly more of the genetic risk for alcohol dependence among women than among men (Slutske et al 2002
). Second, these associations may be modified by age. For example, 1) the relationship between rigidity and alcohol consumption was found to be modified by age; it appears that a rigid adolescent refrains from drinking a second, third, or fourth drink, whereas a rigid young adult refrains from initiating drinking; in adulthood, rigid persons are less subject to influence to drink (Koppes et al 2001
); and 2) in women only, especially adults, dominance was positively related to the level of wine consumption (Koppes et al 2001
Single nucleotide polymorphism 2 (SNP2) is a nonsynonymous variant (Gly→Arg) in exon 9. Single nucleotide polymorphism 2 is in strong LD with SNP6 and was, like SNP6, strongly associated with SD (Luo et al 2005b
). Single nucleotide polymorphism 2 was also the marker closest to the risk locus for drug dependence (Luo et al 2005b
). In this study, SNP2 was associated with extraversion, although this association appeared only in subjects with higher conscientiousness scores. Single nucleotide polymorphism 1 had similar effects to those of SNP2. The modulating role of conscientiousness in the effects of SNPs 1 and 2 on extraversion indicates that there was a strong correlation between these two personality traits, and that this correlation makes it difficult to detect gene effects on extraversion independent of conscientiousness; thus, this correlation needs to be considered in studying these gene effects.
Both SD (Luo et al 2005b
) and personality traits (present article) were demonstrated to be strongly associated with ADH4
. We, therefore, conclude that personality traits and SD have a partially shared genetic basis, consistent with the extant literature. Both phenotypes are influenced by the environment as well. It is probable that being substance dependent exerts some influence on personality structure during the course of the illness (Verheul et al 2004
). If the influence of ADH4
variation on personality were mediated through an effect on SD (that is, if it were a secondary phenomenon), then findings in substance dependent subjects would be expected to differ from those in control subjects. We therefore divided the subjects into case and control groups and tested the relationship between ADH4
and personality within each group, and most of the results were similar (data not shown). That is, diagnosis does not generally affect the relationship between ADH4
and personality. Thus, some specific personality traits could be taken as phenotypes independent of SD, though mediated by ADH4
as SD. This is understandable because personality traits might have some underlying neurobiological mechanisms similar to those influencing risk for SD. The ADH4 enzyme (π ADH) catalyzes certain endogenous substrates (i.e., norepinephrine aldehydes, including 3,4-dihydroxymandelaldehyde [DHMAL] and 4-hydroxy-3-methoxymandelaldehyde [HMMAL]) to synthesize the intermediary glycols of norepinephrine metabolism, including 3,4-dihydroxyphenylglycol (DHPG) and 4-hy-droxy-3-methoxyphenylglycol (HMPG), respectively. The enzyme π ADH has 9- to 29-fold greater efficiency as a catalyst for this reaction than any class I isozyme (α, β, and γ ADHs); class III ADH (χ ADH) does not have any detectable catalytic activity for these substrates (Mardh et al 1986
). Activated π ADH attributable to ADH4
gene variation, e.g., allele A of SNP6 (Edenberg et al 1999
), would be predicted to increase levels of DHPG and HMPG, and this could result in a very high turnover of norepinephrine aldehydes. To block the turnover of norepinephrine aldehydes, an individual could self-administer alcohol to compete with DHPG and HMPG anabolism, because alcohol is an exogenous competitor for endogenous DHPG and HMPG on π ADH (Mardh et al 1986
). Over time, this could lead to alcohol dependence. Alternatively, to mitigate the lower norepinephrine levels, an individual could self-administer cocaine, which partially functions as a norepinephrine reuptake inhibitor and can increase plasma norepinephrine concentrations (Sofuoglu et al 2001
), or opiates, which stimulate norepinephrine release in cerebrospinal fluid (Bouaziz et al 1996
). Over time, such self-administration of drugs (cocaine and opiates) could, similarly, lead to drug dependence. Norepinephrine is also well known to play a role in the development and expression of various personality traits (Coccaro et al 2003
). A low level of norepinephrine is usually hypothesized to cause aggressive behavior (Coccaro et al 2003
) that could be most closely predicted by (low) agreeableness (Gleason et al 2004
). Agreeableness-related personality traits and aggression might be the outcome of a self-regulatory process predicated on a low level of norepinephrine (Gleason et al 2004
). Thus, personality trait development might have a similar mechanism to SD risk, potentially mediated by norepinephrine levels, which are affected by ADH4 enzyme activity. Alternatively, other mechanisms via other pathways, e.g., a dopaminergic pathway, might be possible.