The association between DRD2/ANKK1 and genetically informed measures of alcohol use and problems

Abstract

Background In 1990, Blum and colleagues first reported an association between DRD2 and alcoholism. While there have been subsequent replications of this genetic association, there have also been numerous studies that failed to detect an association between DRD2 and alcohol dependence. We propose that one aspect contributing to this inconsistency is the variation in alcohol phenotype used across studies. Methods Within the population based Finnish twin sample, FinnTwin16, we previously performed multivariate twin analyses to extract latent genetic factors which account for the variation across seven measures of alcohol consumption (frequency of drinking, frequency × quantity, frequency of heavy drinking, frequency of intoxication, and maximum drinks in a 24 hour period) and problems (the Rutgers Alcohol Problem Index-RAPI and the Mälmö-modified Michigan Alcohol Screen Test - MmMAST) in 3,065 twins. In the present study, we examined the association between thirty-one DRD2/ANKK1 SNPs and the genetic factor scores generated by twin analyses in a subset of FinnTwin16 (n=602). We focus on two of the genetic factors: a general alcohol consumption and problems factor score which represents shared genetic variance across alcohol measures, and an alcohol problems genetic factor score which loads onto the two indices of problematic drinking (MAST and RAPI). Results After correction for multiple testing across SNPs and phenotypes, of the thirty-one SNPs genotyped across DRD2/ANKK1, one SNP (rs10891549) showed significant association with the general alcohol consumption and problems factor score (p=0.004), and four SNPs (rs10891549, rs1554929, rs6275, rs6279), representing 2 independent signals after accounting for LD, showed significant association with the alcohol problems genetic factor score (p=0.005, p=0.005, p=0.003, p=0.003). Conclusions In this study, we provide additional positive evidence for the association between DRD2/ANKK1 and alcohol outcomes, including frequency of drinking and drinking problems. Additionally, post hoc analyses indicate stronger association signals using genetic factor scores than individual measures, which suggests that accounting for the genetic architecture of the alcohol measures reduces genetic heterogeneity in alcohol dependence outcomes in this sample and enhances the ability to detect association.

Beta-amyloid auto-antibodies are reduced in Alzheimer's disease

“…A1 mutation of ANKK1 gene has been associated with alcoholism, smoking and drug addiction [34,35]. The relationship of this mutation with AD has not been reported.…”

Candidate Gene–Environment Interaction Research

“…Further, when a gene of interest is being studied, genetic variants across the gene are usually genotyped in order to capture the many locations across that gene that could be involved 2 in altering gene regulation or function and producing different effects on behavior. For example, many early studies genotyped the Taq1A1 polymorphism in DRD2 as a hypothesized biological candidate for a variety of outcomes related to reward deficiency, for which dopamine transmission was thought to play a role (Blum et al, 1990; Meyers et al, 2013; Young, Lawford, Nutting, & Noble, 2004). Subsequently, it was discovered that the polymorphism was actually located in the neighboring gene ANKK1 (Neville, Johnstone, & Walton, 2004).…”

Association between Polymorphisms of the DRD2 and ANKK1 Genes and Suicide Attempt: A Preliminary Case-Control Study in a Mexican Population

“…There is an important number of functional polymorphisms identified in this gene. One of them is rs6275, also known as 939C/T at nucleotide location 939, which is associated with heroin [15] and alcohol [16] dependence; likewise, it is associated with attention functions in schizophrenia [17, 18]. Another polymorphism of this gene is rs1799978 or –241A/G; that results in a substitution of adenine for guanine at location –241 of the promoter region.…”