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

Abstract

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 disorder (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 of subjects (literature-based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding 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 all 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 ADHD than either the dopaminergic or serotonergic genes combined. The results using literature-based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

“…In three SPECT studies of adults with ADHD, elevated levels of DAT protein were detected, but genotyping was not performed in this cohort. 12,13,14 As ADHD is most likely polygenic, [70][71][72] and the association of the 10-repeat length allele accounts for only 3.6% of the variance in hyperactive-impulsive symptoms and 1.1% of the variance in inattentive symptoms in ADHD, 31 it is unlikely that a robust association between DAT (length) genotype and DAT density would emerge. A detailed analysis of the frequency of SNPs throughout human 10-repeat length-containing alleles is needed to further investigate DAT gene polymorphisms and ADHD, as well as other dopamine-related disorders.…”

An examination of the behavioral and neuropsychological correlates of three ADHD candidate gene polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive and normal children followed to adulthood

“…The greatest research has been on DRD4 with 7 repeats and the DAT1 40bp VNTR (Comings et al 1991, Cook et al 1995, Comings et al 1996, LaHoste et al 1996, Gill et al 1997, Swanson et al 1997, Castellanos et al 1998, Smalley et al 1998, Swanson et al 1998, Daly et al 1999, Farone et al 1999, Rowe et al 1999, Comings et al 2000, Eisenberg et al 2000, Kotler et al 2000, Muglia et al 2000, Tahir et al 2000 . Cook et al (1995) was among the first to find preferential transmission of the 40bp allele (allele 3) of a VNTR in the 3′ UTR of the DAT1 40bp VNTR gene (12p12.3), a finding replicated by others, but not all investigators (Gill et al 1997, Daly et al 1999).…”

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB

“…Finally, it has been reported that SLC6A4 together with the serotonin receptor 5HT1A and the tryptophan hydroxylase gene (TPH1) accounted for 3.09% of ADHD variance. 45 Based on all these data, we hypothesized that alterations in serotonin neurotransmission may be involved in genetic susceptibility to ADHD, and that common risk variants may participate in both childhood and adulthood ADHD. To address these issues, we ran a population-based association study in 451 ADHD patients (188 adults and 263 children) and 400 controls, with single nucleotide polymorphisms (SNPs) covering 19 candidate genes that encode serotonin receptors (5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F, 5HT2A, 5HT2B, 5HT2C, 5HT3A, 5HT3B, 5HT4, 5HT5A, 5HT6 and 5HT7), the serotonin transporter (SLC6A4) and enzymes involved in serotonin synthesis (TPH1 and DDC) and degradation (MAOA and MAOB).…”