Am J Med Genet (Neuropsychiatric Genetics) 67(3): 264-288 (1996)
Polygenic Inheritance of Tourette Syndrome, Stuttering, Attention Deficit Hyperactivity, Conduct, and Oppositional Defiant Disorder:
The Additive and Subtractive Effect of the Three Dopaminergic Genes—DRD2, DβH, and DAT1

David E. Comings, S. Wu, Connie Chiu, Robert H. Ring, Radhika Gade, Chul Ahn, James P. MacMurray, George Dietz, and Donn Muhleman

Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine β-hydroxylase (DβH), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse, and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.

*LOD stands for "logarithm of the odds." In genetics, the LOD score is a statistical estimate of whether two genes, or a gene and a disease gene, are likely to be located near each other on a chromosome and are therefore likely to be inherited together.

Correlation by specific behaviors may be the most powerful approach for psychiatric genetics. The above considerations, plus the fact that linkage studies, whether by lod* score, sib pair analysis, or the haplotype relative risk technique, may be too inefficient for identifying the effect of polygenes, suggests that the present approach of examining the effect of a gene in question on the degree of expression of a number of specific behavioral variables may be the most powerful technique available for psychiatric genetics. This is supported by our results with the dopamine β-hydroxylase and dopamine transporter where there were minimal or no significant differences in allele frequencies or prevalences between controls and TS subjects, but highly significant differences for some of the individual behaviors.

Expected variability of results. The nature of polygenic inheritance, and the low percentage of variance accounted for by a single gene, suggests that different sets of genes will be involved in different subjects, different studies, and different sets of patients performed in different geographical locations. Thus, significant variations between different studies should be the rule rather than the exception. For example, one study done in Germany showed no association between the DzAl allele and alcoholism [Schwab et al., 1991] while a study done in a neighboring country, France, showed a striking difference in DzAl frequency in controls versus alcoholics [Amadeo et al., 1993]. The final truth about the role of a given gene in a given disorder, or a given behavior, may have to await the completion of a number of studies followed by a metanalysis of the total set [Schmidt, 1992].