A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence

Wang, Fan; Simen, Arthur A.; Arias, Albert J.; Lu, Qunwei; Zhang, Huiping

doi:10.1007/s00439-012-1251-6

Cited by 76 publications

(55 citation statements)

References 90 publications

(118 reference statements)

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“…However, candidate gene studies are known to be prone to type I errors. When systematic meta-analysis of the literature is conducted, evidence of association with substance use/abuse is equivocal; metaanalyses looking at rs1800497 in relation to smoking [61,62] and alcohol [63,64] have been mixed, with effects possibly being population, gender or substance-specific.…”

Section: Replication Of Previous Findingsmentioning

confidence: 99%

The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

Hodgson

Almasy

Knowles

et al. 2017

European Neuropsychopharmacology

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Background and aims-While the prevalence of major depression is elevated amongst cannabis users, the role of genetics in this pattern of comorbidity is not clear. This study aimed to estimate the heritability of cannabis use and major depression, quantify the genetic overlap between these two traits, and localize regions of the genome that segregate in families with cannabis use and major depression.

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Section: Replication Of Previous Findingsmentioning

confidence: 99%

The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

Hodgson

Almasy

Knowles

et al. 2017

European Neuropsychopharmacology

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“…Indeed, genetic and epigenetic aberrations in dopamine D2 receptors (D2Rs), GABA B Rs, μ opioid receptors, and serotonin 1A receptors (5-HT 1A Rs), have been implicated in alcohol dependence in human alcoholics (6)(7)(8)(9)(10). Recently, preclinical evidence has indicated that the rewarding properties of multiple drugs of abuse can be ameliorated by activation of GABA B Rs in the VTA (7,11).…”

Section: Rgs6mentioning

confidence: 99%

Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Stewart¹,

Maity²,

Anderegg³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol is the most commonly abused drug worldwide, and chronic alcohol consumption is a major etiological factor in the development of multiple pathological sequelae, including alcoholic cardiomyopathy and hepatic cirrhosis. Here, we identify regulator of G protein signaling 6 (RGS6) as a critical regulator of both alcohol-seeking behaviors and the associated cardiac and hepatic morbidities through two mechanistically divergent signaling actions. RGS6−/− mice consume less alcohol when given free access and are less susceptible to alcohol-induced reward and withdrawal. Antagonism of GABAB receptors or dopamine D2 receptors partially reversed the reduction in alcohol consumption in RGS6−/− animals. Strikingly, dopamine transporter inhibition completely restored alcohol seeking in mice lacking RGS6. RGS6 deficiency was associated with alterations in the expression of genes controlling dopamine (DA) homeostasis and a reduction in DA levels in the striatum. Taken together, these data implicate RGS6 as an essential regulator of DA bioavailability. RGS6 deficiency also provided dramatic protection against cardiac hypertrophy and fibrosis, hepatic steatosis, and gastrointestinal barrier dysfunction and endotoxemia when mice were forced to consume alcohol. Although RGS proteins canonically function as G-protein regulators, RGS6-dependent, alcohol-mediated toxicity in the heart, liver, and gastrointestinal tract involves the ability of RGS6 to promote reactive oxygen species-dependent apoptosis, an action independent of its G-protein regulatory capacity. We propose that inhibition of RGS6 might represent a viable means to reduce alcohol cravings and withdrawal in human patients, while simultaneously protecting the heart and liver from further damage upon relapse.

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“…Perhaps the best-known example is the association of the Taq1A allele of the dopamine D 2 receptor gene ( DRD2-Taq1A; rs1800497) with alcohol disorder, which was first reported in a small study in 1990 [83,84]. Numerous groups have attempted to replicate this finding, but most replication studies have yielded negative or inconclusive results [85,86,87,88,89,90].…”

Section: Candidate Gene Studiesmentioning

confidence: 89%

“…A recent meta-analysis has suggested a small but significant effect. The authors cautioned that the positive result might have been caused by publication bias [91], but a more recent meta-analysis by a different group has confirmed the association and largely ruled out publication bias [84]. The example of rs1800497 highlights another important problem of genetic association studies, namely that inconclusive results can result from linkage disequilibrium with other variants that might actually be causally related to a phenotype (Note: linkage disequilibrium refers to the nonrandom association and coupled inheritance of allelic variants at two loci that may or may not have a large genetic distance [92]).…”

Section: Candidate Gene Studiesmentioning

confidence: 99%

Genetics of Alcohol Dependence: A Review of Clinical Studies

Samochowiec

Puls

et al. 2014

Neuropsychobiology

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Background/Aims: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. Methods: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). Results: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. Conclusion: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.

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A large-scale meta-analysis of the association between the ANKK1/DRD2 Taq1A polymorphism and alcohol dependence

Cited by 76 publications

References 90 publications

The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

The Genetic Basis Of The Comorbidity Between Cannabis Use And Major Depression

Regulator of G protein signaling 6 is a critical mediator of both reward-related behavioral and pathological responses to alcohol

Genetics of Alcohol Dependence: A Review of Clinical Studies

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