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

Abstract

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. © 1996 Wiley‐Liss, Inc.

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).…”

Association of polymorphisms of dopamine D2 receptor (DRD2), and dopamine transporter (DAT1) genes with schizoid/avoidant behaviors (SAB)

“…15 Molecular genetic evidence on the role of dopamine in reward axial Inventory (MCMI-II). 43,44 and the B 1 allele of dopacal scales was constructed as an operational measure of a syndrome derived from a theory of personality and mine beta hydroxylase gene (D␤H) also associated with Tourette's disorder and a number of behavioral subpsychopathology. The clinically oriented scales are coordinated directly with the official diagnostic system traits.…”

“…The clinically oriented scales are coordinated directly with the official diagnostic system traits. 44 The DRD 2 gene is localized to chromosome 11 q22-and its syndrome categories (DSM-IV). Separate scales have been constructed in line with the DSM-IV model 23, the D␤H gene is localized to chromosome 9 q34 and the human dopamine transporter gene first cloned by to distinguish the more enduring personality characteristics of patients (Axis II) from the acute clinical disVandenberg et al 45 has been mapped to chromosome 5 pL 5.3.…”