Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder

Abstract

In a previous study (Comings DE et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178-196) we examined the role of 20 dopamine, serotonin and norepinephrine genes in attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), using a multivariate analysis of associations (MAA) technique. We have now brought the total number of genes examined to 42 by adding an additional 22 candidate genes. These results indicate that even with the inclusion of these additional genes the noradrenergic genes still played a greater role in ADHD than any other group. Six other neurotransmitter genes were included in the regression equation - cholinergic, nicotinic, alpha 4 receptor (CHNRA4), adenosine A2A receptor (ADOA2A), nitric oxide synthase (NOS3), NMDAR1, GRIN2B, and GABRB3. In contrast to ADHD and ODD, CD preferentially utilized hormone and neuropeptide genes These included CCK, CYP19 (aromatase cytochrome P-450), ESR1, and INS (p = 0.005). This is consistent with our prior studies indicating a role of the androgen receptor (AR) gene in a range of externalizing behavors. We propose that the MAA technique, by focusing on the additive effect of multiple genes and on the cummulative effect of functionally related groups of genes, provides a powerful approach to the dissection of the genetic basis of polygenic disorders.

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.…”

A genome-wide screen for genes influencing conduct disorder

“…36 Another study conducted multivariate linear regression analyses to test the relationship of more than 40 candidate genes in ADHD, ODD, and conduct disorder symptomatology in a casecontrol sample of patients with Tourette syndrome. 37,38 Genes were studied in the dopaminergic, serotonergic, adrenergic, and GABAergic pathways, as well as hormone/neuropeptide genes, opioid genes, and other neurotransmitter genes. Associations were found with many genes from each of the above categories; however, conduct disorder was more likely to be associated with hormone/neuropeptide genes than either ADHD or ODD.…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…210 Accumulating evidence suggests that cholinergic system dysregulation contributes to the pathophysiology of ADHD, based on animal, pharmacological and imaging studies. 20,211,212 215 and rs3787141. 211 Some of these findings were not replicated by other groups (for example, Bobb et al 216 ).…”