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Activation of the mesolimbic dopamine pathway appears to promote drug- and alcohol-seeking behavior in laboratory animals. Results for association and linkage analysis between various alcohol dependence phenotypes and the dopamine receptors have been quite mixed. Similarly, both positive and negative results have been presented concerning dopamine receptor genes and temperament. Cloninger has postulated that the novelty seeking factor from the Tridimensional Personality Questionnaire (TPQ) may be related to the dopamine neurotransmitter system. As novelty seeking is a trait of some importance for substance-dependent individuals, our goal was to test this relationship within a sample of families of alcoholics. No evidence favoring linkage between D2, D4, or DAT1 was found for TPQ novelty seeking. However, the harm-avoidance trait from the TPQ showed evidence for linkage to both the D4 and one of the D2 loci (TaqI A). The Multidimensional Personality Questionnaire (MPQ) was used to provide converging evidence for these results. The TPQ harm-avoidance scale loads heavily on introversion (worry, pessimism, shyness), characteristics that may be especially salient in alcoholic families. Thus, planned comparisons were made between selected MPQ traits measuring the affective dimension (negative affectivity, stress reaction, alienation, and well-being). We find evidence favoring linkage between the D2 and D4 receptor loci and these MPQ traits, with stronger evidence being seen for the D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:634-641, 1999.

The purpose of the present study was to evaluate two polymorphisms near the D2 receptor gene (TaqI A RFLP and C microsatellite) and a VNTR for D4. A nonparametric linkage (NPL) technique, SIBPAL, was used to test for the presence or absence of linkage in 54 multiplex alcoholic families. These families had been ascertained through two alcoholic proband siblings in order to increase the density of alcoholic cases within these pedigrees. Phenotypic definitions of alcoholism were manipulated in an effort to determine the impact of severity (signs of physical dependence, early age of onset, presence of antisocial personality disorder) on the likelihood of finding positive evidence for linkage. A regression analysis that simultaneously evaluated the allele sharing identical by descent for Feighner criteria alcoholism in affected, unaffected, and discordant sib pairs (SIBPAL) for two D2 polymorphisms and the D4 polymorphism gave no evidence for linkage. Phenotypes associated with greater alcoholism severity (presence of physical dependence symptoms, earlier onset, or comorbid antisocial personality disorder) revealed some evidence for linkage. The presence of one or more physical dependence symptoms in combination with Feighner criteria alcoholism provided some evidence favoring linkage (TaqI A and D4). Alcoholics with an earlier onset of alcoholism showed some evidence for linkage especially when the presence of physical dependence was required (e. g., morning drinking, wanted to stop drinking but could not, binges or benders, and evidence of withdrawal symptoms). Finally, alcoholics with antisocial personality disorder differed significantly in their allele sharing from nonalcoholics for both D2 polymorphisms. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:676-685, 1999.

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