Association of the A1 allele of the D2 dopamine receptor gene with severe alcoholism

doi:10.1016/0741-8329(91)90693-Q

Alcohol

Volume 8, Issue 5, September–October 1991, Pages 409-416

https://doi.org/10.1016/0741-8329(91)90693-Q Get rights and content

In a blinded study, 159 subjects composed of nonalcoholics (N = 43), less severe alcoholics (N = 44), severe alcoholics (N = 52) and young children of alcoholics (CoAs, N = 20) were studied for their allelic association with the D₂ dopamine receptor (D2DR) gene utilizing peripheral lymphocytes as the DNA source. The combined alcoholic group compared to the nonalcoholic group showed a significantly greater association with the A1 allele of the D2DR gene. Furthermore, an even more robust association was found when severe alcoholics were compared to nonalcoholics. CoAs also showed a significantly greater association with the A1 allele than nonalcoholics but not when compared to alcoholics. Analysis of risk of alcoholism severity suggests that it comprises of two independent components: family history of alcoholism and presence of the A1 allele. Genotype and allelic frequency of the D2DR gene were also analyzed with respect to race. A higher percentage of blacks compared to whites had the A1/A1 genotype, and A1 allelic frequency in the total sample of blacks was significantly greater than in the total sample of whites. Moreover, frequency of the A1 allele was significantly greater in severe alcoholics compared to nonalcoholics in both whites and blacks. However, due to the small sample size of blacks, these racial differences need to be further studied. This study, of the largest sample of alcoholics to date, strongly affirms association of severe alcoholism with the A1 allele of the D2DR gene.

References (38)

HanahanD.
Studies on transformation of Escherichia coli with plasmids
J. Mol. Biol.
(1983)
MidanikL.
Familial alcoholism and problem drinking in a national drinking practices survey
Addict. Behav.
(1983)
St. ClairD. et al.
Association with a family of a balanced autosomal translocation with major mental illness
Lancet
(1990)
BegleiterH. et al.
Event-related brain potentials in boys at risk for alcoholism
Science
(1984)
BlumK. et al.
Allelic association of human dopamine D₂ receptor gene in alcoholism
J. Am. Med. Assoc.
(1990)
BlumK. et al.
Ethanol and neuromodulator interactions: A cascade model of reward
Prog. Alcohol Res.
(1990)
BolosA.M. et al.
Population and pedigree studies reveal a lack of association between the dopamine D₂ receptor gene in alcoholism
J. Am. Med. Assoc.
(1990)
CochranW.B.
Some methods for strengthening the common χ² tests
Biometrics
(1954)
CottonN.S.
The familial incidence of alcoholism: A review
J. Stud. Alcohol
(1979)
ComingsD.E. et al.
Controlled family history study of Tourette's Syndrome II: Alcoholism, drug abuse and obesity
J. Clin. Psychiatry
(1990)

DevorE.J. et al.

Genetics of alcoholism

Annu. Rev. Genet.

(1989)

Di ChiaraG. et al.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

GilliganS.B. et al.

Etiologic heterogeneity in alcoholism

Genet. Epidemiol.

(1987)

GoodwinD.W. et al.

Alcohol problems in adoptees raised apart from alcoholic biological parents

Arch. Gen. Psychiatry

(1973)

GrandyD.K. et al.

The human dopamine D₂ receptor gene is located on chromosome 11 at q22–q23 and identified as TaqI RLFP

Am. J. Hum. Genet.

(1989)

GrandyD.K. et al.

Cloning of the cDNA and gene for a human D₂ dopamine receptor

HillS.Y. et al.

Association and linkage between alcoholism and eleven serological markers

J. Stud. Alcohol

(1975)

HillS.Y. et al.

Genetic linkage analyses of families of alcoholic probands

Cited by (187)

Analysis of ANKKI (rs1800497) and DRD2 (rs1079597, rs1800498) variants in five ethnic groups from Punjab, North-West India
2016, Gene
Dopamine D2 receptor (DRD2) is one of the essential neurotransmitters in the brain studied extensively in the field of psychiatric disorders, alcoholic behaviors and Pharmacology. It is also a promising gene for studying the evolutionary and genetic variation among populations. The present study was an attempt to understand the extent of genetic variation among five different ethnic groups (Bania, Brahmin, Jat Sikh, Khatri and Scheduled caste) of Punjab (North West India). A total of 1012 individuals belonging to the above mentioned groups were analyzed for three TaqI Polymorphic loci of DRD2 and ankyrin repeat and kinase domain containing 1 (ANKKI) using the allele frequencies and haplotype frequency distribution pattern. All the three loci were found to be polymorphic among the studied populations. The average heterozygosity for all loci in these ethnic groups was fairly substantial ranging from 0.3936 to 0.4986. The genetic differentiation among the population was observed to be in order of 0.0053.Among of the eight studied haplotypes, only six were shared by all the ethnic groups. TaqID and TaqIB loci were reported to be in significantly higher linkage disequilibrium (LD) in Scheduled Caste only, whereas TaqIA and TaqID showed modest LD in Brahmin, Jat Sikh and Khatri. Multidimensional scaling analysis revealed that the studied ethnic groups formed a close cluster, suggesting similar genetic structure of these populations which are in close proximity with other Indo European speaking North Indian and western Indian population groups. Overall this study highlights the genomic uniformity among the ethnic groups of Punjab (North-West India) owing to their common ancestral history and geographical closeness.
Sibling genes as environment: Sibling dopamine genotypes and adolescent health support frequency dependent selection
2015, Social Science Research
While research consistently suggests siblings matter for individual outcomes, it remains unclear why. At the same time, studies of genetic effects on health typically correlate variants of a gene with the average level of behavioral or health measures, ignoring more complicated genetic dynamics. Using National Longitudinal Study of Adolescent Health data, we investigate whether sibling genes moderate individual genetic expression. We compare twin variation in health-related absences and self-rated health by genetic differences at three locations related to dopamine regulation and transport to test sibship-level cross-person gene–gene interactions. Results suggest effects of variation at these genetic locations are moderated by sibling genes. Although the mechanism remains unclear, this evidence is consistent with frequency dependent selection and suggests much genetic research may violate the stable unit treatment value assumption.
A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry
2015, Psychiatric Clinics of North America
Citation Excerpt :
The allelic form (A1 vs A2) of the DRD2 gene is responsible for the expression of receptors at postjunctional sites. The A1 form results in hypodopaminergic function,83,141 and in people, a paucity of DA receptors are predisposed to seek any substance or behavior that stimulates the dopaminergic system.142 The neurotransmitter DA and the DRD2 gene, despite controversy,143 have long been associated with reward.14
Differential effects of oxycodone, hydrocodone, and morphine on the responses of D2/D3 dopamine receptors
2015, Behavioural Brain Research
Citation Excerpt :
Specifically, the D2L splice variant of the receptor was demonstrated to be essential for the rewarding properties of morphine [10,11]. In addition, association has been observed between D2 receptor genes and the abuse of various illicit drugs, as well as between D2 receptor genes and alcoholism [12–14]. Moreover, the D2DRs were also suggested to be involved in the pathophysiology of affective and psychotic disorders [15–17].
Oxycodone and hydrocodone are opioids which are widely used for pain management and are also commonly misused and abused. The exposure to opioid analgesics has been associated with altered responses of D2-like dopamine receptors (D2DRs). Our recent results suggest that various opioids will differentially modulate the responses of D2DRs. The D2DRs are known to be involved in the pathology of addiction and other mental illnesses, indicating the need to improve our understanding of the effects of opioid analgesics on the responses of the D2DRs. Thus, in this study, we first established equianalgesic oral doses of oxycodone, hydrocodone, and morphine using the tail withdrawal assay. Then, mice were orally administered (gavage) with the various opioids or saline once daily for 6 days. Twenty-four hours later, the mice were tested for their locomotor response to quinpirole, a D2/D3 dopamine receptor agonist. Mice pretreated with oxycodone showed significantly greater locomotor supersensitivity to quinpirole than did morphine-pretreated mice, while hydrocodone-pretreated mice showed sensitivity in between that of mice treated with morphine and oxycodone. This finding suggests that various opioids differentially modulate the responses of D2DRs. It provides further evidence supporting of the notion that various opioids carry differential risks to the dopamine reward system.
Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior
2014, Medical Hypotheses
Citation Excerpt :
This breakdown of the reward cascade, [33–41] due to specific genetic and environmental influences, [42] that result in aberrant conduct, is referred to as RDS. It is well known that abuse of psychoactive drugs including; alcohol, [43] as well as most positive reinforcers like sex, food, gambling and aggression activate the release of neuronal dopamine [44–56] which can satisfy abnormal cravings [46] and increase positive feelings [57]. A deficiency of D2 receptor then predisposes individuals to multiple addictive, impulsive, and compulsive behaviors [58–60].
The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD.
Variation of types of alcoholism: Review and subtypes identified in Han Chinese
2014, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Citation Excerpt :
However, the association between alcoholism and the DRD2 gene, with special attention to the A polymorphism, remains inconsistent. A number of studies (Blum et al., 1991; Noble, 1994) reported an association between alcoholism and the DRD2 gene; however, the association is not universally supported (Bolos et al., 1990; Gejman et al., 1994; Gelernter et al., 1991; Suarez et al., 1994; Turner et al., 1992) and remains controversial (Conneally, 1991). Edenberg et al. (1998) concluded that neither studies using the transmission disequilibrium test nor those using the affected family-based association test found any association between the DRD2 gene and alcoholism.
Alcoholism, as it has been hypothesized, is caused by a highly heterogeneous genetic load. Since 1960, many reports have used the bio-psycho-social approach to subtype alcoholism; however, no subtypes have been genetically validated. We reviewed and compared the major single-gene, multiple-gene, and gene-to-gene interaction studies on alcoholism published during the past quarter-century, including many recent studies that have made contributions to the subtyping of alcoholism. Four subtypes of alcoholism have been reported: [1] pure alcoholism, [2] anxiety/depression alcoholism, [3] antisocial alcoholism, and [4] mixed alcoholism. Most of the important studies focused on three genes: DRD2, MAOA, and ALDH2. Therefore, our review focuses on these three genes.

View all citing articles on Scopus

View full text

Rapid communicationAssociation of the A1 allele of the D2 dopamine receptor gene with severe alcoholism

J. Mol. Biol.

Addict. Behav.

Lancet

Event-related brain potentials in boys at risk for alcoholism

Science

Allelic association of human dopamine D2 receptor gene in alcoholism

J. Am. Med. Assoc.

Ethanol and neuromodulator interactions: A cascade model of reward

Prog. Alcohol Res.

Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene in alcoholism

J. Am. Med. Assoc.

Some methods for strengthening the common χ2 tests

Biometrics

The familial incidence of alcoholism: A review

J. Stud. Alcohol

Controlled family history study of Tourette's Syndrome II: Alcoholism, drug abuse and obesity

J. Clin. Psychiatry

Genetics of alcoholism

Annu. Rev. Genet.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Etiologic heterogeneity in alcoholism

Genet. Epidemiol.

Alcohol problems in adoptees raised apart from alcoholic biological parents

Arch. Gen. Psychiatry

The human dopamine D2 receptor gene is located on chromosome 11 at q22–q23 and identified as TaqI RLFP

Am. J. Hum. Genet.

Cloning of the cDNA and gene for a human D2 dopamine receptor

Association and linkage between alcoholism and eleven serological markers

J. Stud. Alcohol

Genetic linkage analyses of families of alcoholic probands

Rapid communication
Association of the A1 allele of the D₂ dopamine receptor gene with severe alcoholism

Allelic association of human dopamine D₂ receptor gene in alcoholism

Population and pedigree studies reveal a lack of association between the dopamine D₂ receptor gene in alcoholism

Some methods for strengthening the common χ² tests

The human dopamine D₂ receptor gene is located on chromosome 11 at q22–q23 and identified as TaqI RLFP

Cloning of the cDNA and gene for a human D₂ dopamine receptor