The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample

Abstract

Background: Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples.Methods: In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD.Results: PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Dmarginal R 2 = 1.39%, D area under the curve [AUC] = 0.011), DSM4AD (Dmarginal R 2 = 0.56%; DAUC = 0.003), DSM5AUDSX (Dmarginal R 2 = 0.49%), MAXD (Dmarginal R 2 = 0.31%), and SRE-T (Dmarginal R 2 = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08eÀ5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Dmarginal R 2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant.Conclusions: Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking.

High‐Intensity Drinking in Adult Australian Twins

“…Of interest is the repeated finding from multivariate twin studies that different alcohol use phenotypes, such as the quantity and frequency of alcohol use and max drinks, have overlapping, but distinct, genetic architectures (Agrawal et al, ; Dick et al, ; Kendler et al, ). Consistent with this is recent genomic evidence demonstrating that max drinks are only modestly predicted from a polygenic risk score for weekly alcohol consumption derived in an independent sample (Johnson et al, ). These findings have also been mirrored in the animal literature.…”

Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples

“…These findings are consistent with the lack of genetic correlation between psychiatric illness and genetic liability to alcohol consumption in the largest GWAS of the trait (drinks per week; Liu et al, 2019). In contrast, two recent studies suggest moderate genetic correlations between AUD and consumption indices, including the AUDIT-C (e.g., r g = 0.52, p = 2.40e-42) (Kranzler et al, 2019;Marees et al, 2019), while another study found that polygenic risk scores (PRS) for past week alcohol consumption predicted a modest but significant amount of variance in AUD (e.g., R 2 = 0.56%; Johnson et al, 2019), suggesting that the genetic correspondence between recent consumption and dependence may be complicated by several factors, including the characteristics of the sample, and the nature of the assessment (e.g., alcohol quantity vs. frequency (Marees et al, 2019)).…”

“…We also hypothesized that associations with AUDIT-C would be stronger in the youngest sample while the AUDIT-P would be more predictive of drinking in older, ascertained samples in which problem drinking is more established. While there have been some recent studies examining the genetic overlap between alcohol consumption and indices of problem drinking (e.g., Johnson et al, 2019), none have yet compared the performance of consumption (AUDIT-C) versus problem drinking (AUDIT-P) PRS across multiple samples. Taken together, the current analyses demonstrate how genetic findings derived from a simple and fast screening tool could serve to outline the polygenic 6 underpinnings of different stages of alcohol use and problems in diversely ascertained samples.…”

Genome‐wide association studies of the self‐rating of effects of ethanol (SRE)

“…Genetic analyses of the average SRE scores across the three time periods (SRE‐T) have been limited to candidate gene studies . A recent analysis showed that polygenic risk scores derived from a GWAS of alcohol consumption in a large UK population of older adults explained minimal variance in SRE‐T suggesting that even at a polygenic level, SRE scores might be associated with unique genetic variation. Given the importance of SRE as a predictor of problem drinking, and its role in intervention research, the identification of such variants is necessary.…”