Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes

The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin. and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity diso rder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set or subjects (literature-based scoring), or r esults based on analysis of variance fur the sample (optimized gene scoring ). Multivariate linear regression analysis with backward elimination was us ed to determine which genes contributed most to the phenotype for both codi ng methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p = 0.052; three serotonin genes contributed to 3%, p = 0.015. and six adrenergic genes contributed to 6.9%, p = 0.0006. For al l genes combined, 12 genes contributed to 11.6% of the variance, p = 0.0001 . These results indicate that the adrenergic genes play a greater role in A DHD than either the dopaminergic or serotonergic genes combined. The result s using literature-based gene scoring were similar. An examination of two a dditional comorbid phenotypes, conduct disorder and oppositional defiant di sorder (ODD), indicated they shared genes with ADHD. For ODD different geno types of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.