Ebstein1 first highlighted the saga of an 'adventure gene': the dopamine D4 receptor gene (DRD4) and its association with substance abuse and personality. This was followed with a report by Baron2 who suggested that this saga is sagging due to conflicting reports emerging. It now appears that the saga continues with 'severity of dependence' to substance abuse, another variable that may be pertinent to the DRD4 association.3
In 1996, Ebstein and colleagues4 examined DRD4 and its association with the human personality trait Novelty Seeking (NS) in a sample of healthy volunteers recruited from an unrelated. Israeli staff/student population. Using Cloninger's Tridimensional Personality Questionnaire (TPQ)5 to measure NS (high novelty seekers are characterized by their impulsive and exploratory behaviour), they reported an association between the DRD4 gene and normal human personality. They analyzed TPQ scores and frequency of DRD4 exon III repeat polymorphisms in 124 samples and found that subjects with the seven-repeat allele exhibited significantly higher NS scores when compared to subjects lacking the seven-repeat allele. This association did not appear to be due to population stratification as it was independent of ethnicity, age or sex of the subjects (69 men, 55 women, mean age 29.8 years).
Benjamin et al6 provided support for this initial study by investigating the relationship between the DRD4 exon III sequence variant and personality test scores amongst a sample of 315 American family members and individuals. The study confirmed initial findings of the Ebstein et al study4 despite methodological differences. For example. Benjamin et al used a sample of white Americans, of whom 95% were male. In addition, they employed Eysenck's NEO-PI-R, which is based upon a trait model of personality, with NS falling in the extraversion factor. This is in contrast to the TPQ, which is based on a biological model in which three independent dimensions of temperament are attributed to genetically and neurochemically distinct pathways, with novelty seeking being mediated by dopamine neurotransmission.1 Finally, Benjamin et al6 did not examine presence or absence of the seven-repeat allele, but grouped individual genotypes into long or short alleles on the gene. Subjects with the long alleles were found to be significantly higher novelty seekers than those with the short alleles.
A third study, conducted by Ebstein,1 offered additional evidence for the association with DRD4 and NS, using similar methods to their previous study. In the same year, Ono and colleagues7 conducted a similar study with 153 normal, Japanese women (mean age 18.7 years). They used the TPQ to measure NS and found an association with long alleles at the polymorphic exon III repeats sequence of DRD4 and NS.
Evidence continued to build for the association between DRD4 and NS amongst healthy people with different ethnic origins. To date, a further six studies8,9,10,11,12,13 have been published, making a total of ten studies offering support for this association. One study used a sample of 119, twelve-year-old Caucasian boys,8 there have been two Japanese studies,10,12 a Finnish study,9 an Israeli study13 and a German study11 conducted.
Despite substantial evidence emerging for the association between the DRD4 gene variant and NS, there have been conflicting reports showing a lack of association between these variables,14,15,16,17,18,19,20,21,22,23 which may be attributable to basic methodological differences between studies. Ebstein1 established guidelines for conducting such research and in doing so highlighted the controversy surrounding this association. Baron2 swiftly responded by offering constructive criticism concerning methodological issues surrounding this research, questioning whether the saga of the 'adventure gene' was sagging.
Research refuting the association with DRD4 and NS began in 199614 and was shortly followed by three articles in 1997,18,19,20 four articles in 199815,16,17,23 and two in 1999.21,22 There are several possible reasons as to why these studies failed to find an association with DRD4 and NS. Firstly, age is an important variable to consider in personality research. NS diminishes with age so to obtain consistent personality scores, subjects should be young (ideally under the age of 45 years).24 Reports providing evidence for the association with DRD4 and NS used subjects between the ages of 12-35 years.1,4,6,7,8,9,10,11,12,13 The subjects used in studies that failed to find a significant association with DRD4 and NS were older, between 18-62 years.14,15,16,17,18,19,20,21,22,23 Of these studies reporting negative findings, 60% employed subjects who were over the age of 35 years.17,18,19,20,22,23 It appears that negative results may have been obtained because NS levels were lower in these people because they were older.
Secondly, failure to find an association with DRD4 and NS may be due to the lack of uniformity employed when measuring the personality trait. Scales with high retest reliability and valid for use with a variety of populations and cultures should be used for this research.1 The TPQ Novelty Seeking scale and the ZKPQ Sensation Seeking Scale are suitable and moderately correlated allowing results to be generalized across different studies.3 Failure to find associations with DRD4 and personality traits may be due to authors using different personality scales to measure NS.
Another factor that may be pertinent to the association is ethnicity. So far, studies have used Israeli, Japanese, American, Swedish, Finnish and German populations. The association may be dependent upon ethnicity as genetic variants vary across different ethnic groups. It is possible that the relationship between DRD4 and NS is real, but only in some populations and not others.
Gender is another variable to be considered in light of these conflicting findings. Mixed gender groups of sufficient size should be used for this research. For example, the Japanese replication study observing an association was restricted to women.7 Whereas the Finnish study which did not observe a significant association with DRD4 and NS only included men.14 This controversy may have been due to different gender groups being used in each study.
While the search for a true association with DRD4 and NS continues, the search for genes associated with substance abuse is taking the same theme. Similar conflicting findings are also reported in substance abuse with half of the studies reporting a significant association with the DRD4 gene variant25,26,27,28,29,30 whilst the other half have failed to replicate this association.31,32,33,34,35,36,37,38
The pattern that is emerging is that significant associations between DRD4 and substance abuse are found amongst samples of drug abusers (heroin and nicotine dependence)26,27,29 and non-significant results are yielded from samples of alcohol abusers.31,32,34,35,36,37,38 One study did find a significant association with DRD4 and alcohol abuse but this was only observed in alcohol abusers who were distinguished by the ALDH2 polymorphism.28 ALDH22 (as opposed to ALDH21) is an allele whose presence causes a flushing reaction following alcohol ingestion which therefore acts protectively to lower the incidence of alcoholism in people with this genotype.
Furthermore, diagnosing substance abuse may be another important factor that may influence the results obtained from these association studies. If substance abuse or dependence status is not clearly defined amongst the sample or controls then associations between variables may not be found due to the substance abuse group being too similar to the control group. This issue gives rise to the continuation of the saga with the association between DRD4, substance abuse and NS. A recent study3 measured severity of dependence and failed to support previous findings of a significant association with DRD4 and substance abuse. However, results did suggest that possession of the long-repeat genotype at the DRD4 receptor makes an individual more susceptible to severe dependence upon a substance. This study indicated that substance-dependent subjects who possess the long-repeat genotype rate their severity of dependence significantly higher than those with the short-repeat genotype. It was concluded from this study that the variant at DRD4 does not increase susceptibility to dependence per se, but that the variant may partially determine severity of dependence.3 The lack of association previously reported might have occurred because dependence severity was not analyzed in association with genotype.
To highlight the importance of dependence severity in association studies another study has since reported an association between pathological gambling and the Monamine Oxidase gene (MAOA) polymorphism.39 The study found no significant differences between pathological gamblers and healthy controls in overall allele distribution at the MAOA gene but when severity of gambling was considered they did find a significant association between allele distribution in a subgroup of severe gamblers.
By reviewing this recent research, it can be concluded that there may be an association with DRD4 and NS amongst severe drug-dependent populations. Therefore, the DRD4 gene may not predispose individuals to addiction per se, but having the genetic variant may predispose substance abusers to a severe dependency. Therefore, does the saga continue for the DRD4 gene and its association with NS and substance abuse? As with all sagas we shall have to wait for further developments. Resolution of the saga will depend on methodologically stringent studies. Furthermore, studies may need to account for severity of dependence, another variable that may be important to this association before we can witness the outcome of this saga.
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