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Title: Global distribution of allele frequencies at the human dopamine D4 receptor locus

Abstract

The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).

Authors:
;  [1];  [2]
  1. Yale Univ. School of Medicine, New Haven, CT (United States)
  2. DuPont-Merch Pharmaceutical Company, Wilmington, DE (United States) [and others
Publication Date:
OSTI Identifier:
134652
Report Number(s):
CONF-941009-
Journal ID: AJHGAG; ISSN 0002-9297; TRN: 95:005313-1389
Resource Type:
Journal Article
Resource Relation:
Journal Name: American Journal of Human Genetics; Journal Volume: 55; Journal Issue: Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; GENES; GENE MUTATIONS; MUTATION FREQUENCY; RECEPTORS; DOPAMINE; HUMAN POPULATIONS; MENTAL DISORDERS; NERVOUS SYSTEM DISEASES; EXONS

Citation Formats

Chang, F.M., Kidd, J.R., and Livak, K.J. Global distribution of allele frequencies at the human dopamine D4 receptor locus. United States: N. p., 1994. Web.
Chang, F.M., Kidd, J.R., & Livak, K.J. Global distribution of allele frequencies at the human dopamine D4 receptor locus. United States.
Chang, F.M., Kidd, J.R., and Livak, K.J. 1994. "Global distribution of allele frequencies at the human dopamine D4 receptor locus". United States. doi:.
@article{osti_134652,
title = {Global distribution of allele frequencies at the human dopamine D4 receptor locus},
author = {Chang, F.M. and Kidd, J.R. and Livak, K.J.},
abstractNote = {The dopamine D4 receptor (DRD4) is a candidate gene for schizophrenia because the dopaminergic system has been implicated in this neuropsychiatric disorder. Several research groups have reported an association between allelic variants at DRD4 and schizophrenia, while others have been unable to replicate that finding. Knowledge of the appropriate gene frequencies in the underlying populations may resolve these inconsistencies. We have determined the frequencies of 8 different alleles of the 48 bp imperfect tandem repeat of exon 3 at the DRD4 locus in samples from 33 populations around the world. The frequencies vary considerably in the different populations with the most common allele ranging from 16% to 95%. Frequencies and Fst values will be presented for the 3 most common alleles (4-, 7-, and 2- repeat) by continental groupings, but the individual populations vary significantly around the averages. The populations averaged 4.3 alleles (range 2 to 7).},
doi = {},
journal = {American Journal of Human Genetics},
number = Suppl.3,
volume = 55,
place = {United States},
year = 1994,
month = 9
}
  • Dopaminergic abnormalities are implicated in the pathogenesis of Tourette syndrome (TS) and chronic multiple tics. We used the transmission-disequilibrium test (TDT) method to test for linkage disequilibrium between a specific allele (the seven-repeat allele (DRD4*7R) of the exon 3 VNTR polymorphic site) at the D4 dopamine receptor locus (DRD4) and expression of chronic multiple tics and TS. This particular allele had been shown in functional studies to have different binding properties compared with the other common alleles in this DRD4 polymorphic system. We studied 64 family trios (consisting of an affected person and two parents, at least one heterozygous formore » DRD4*7R), including 12 nuclear family trios and 52 trios from four large TS kindreds. The DRD4*7R allele was transmitted significantly more frequently than expected ({chi}{sup 2}{sub TDT} ranging from 8.47 [P < .004] to 10.80 [P = .001], depending on breadth of disease definition and inclusion or exclusion of inferred genotypes). Confirmation of this finding will depend on either replication in other samples or the identification of a transmitted functional mutation within this sample. 56 refs., 2 figs., 3 tabs.« less
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  • The authors identified a cosmid clone with exact sequence homology to part of the human dopamine D5 receptor gene (DRD5) after screening a cosmid library with the human DRD1 gene. The dopamine D5 receptor was mapped to chromosome 4p15.1-p15.3 by in situ hybridization and using a somatic cell hybrid panel. They report here the further localization of the DRD5 gene following identification of a highly polymorphic dinucleotide repeat sequence in the cosmid clone. The microsatellite (D5(CT/GT/GA)[sub n]) had 12 alleles with a polymorphic information content value of 0.77. Linkage analysis in 39 CEPH pedigrees demonstrated tight linkage to the chromosomemore » 4p reference marker RAF1P1 (Z[sub maxf] 20.66 at [theta][sub f] 0.05 and Z[sub maxM] 16.57 at [theta][sub m] 0.07). 16 refs., 2 tabs.« less
  • Previous studies have indicated the presence of a hereditary component in the generation of the P300, or P3, a late positive component of the event-related potential. Moreover, the dopaminergic system has been implicated in the P3. In the present study, 98 healthy Caucasian boys, mean age of 12.5 years and of above-average intelligence, were studied. The sample was composed of 32 sons of active alcoholic (SAA) fathers, 36 sons of recovering alcoholic (SRA) fathers, and 30 sons of social drinker (SSD) fathers, with none of them having yet begun to consume alcohol or other drugs. TaqI A D[sub 2] dopaminemore » receptor alleles (A1 and A2) were determined. A significant difference in the frequency of the A1 allele was found among these three groups of boys, with the SAA group having the highest A1 allele frequency (.313), followed by the SRA (.139) and the SSD (.133) groups. The relationship of the A1 and A2 alleles to P3 amplitude and latency was also determined. The results showed no significant difference in P3 amplitude between boys with the A1 and A2 allele. However, P3 latency was significantly longer in the total sample of boys with the A1 allele compared with those carrying the A2 allele. These findings suggest that polymorphism of the D[sub 2] dopamine receptor gene is an important determinant of P3 latency. 84 refs., 2 figs., 3 tabs.« less
  • To address the controversy surrounding DRD2 and alcoholism, we performed linkage and association studies utilizing alcoholic men from high density families largely uncontaminated by other psychopathology and female alcoholics for whom secondary drug dependence (averaging 10 years later onset) was a prominent feature. The males and females were combined for a total of 52 alcoholics, and compared to 30 controls screened for the absence of alcoholism and other psychopathology, revealing a significant association between the frequency of the TaqI allele and alcoholism. However, linkage and family-based association study, placed in the context of the literature, suggest that minimizing psychopathology inmore » control groups is probably a more important explanation for divergent results than either sampling error or population stratification. When combined with the complete lack of within-family evidence, we conclude that the association, while not specific to the alcoholism phenotype, per se. 37 refs., 2 tabs.« less