Drinking Motives and Alcohol Sensitivity Mediate Multi-dimensional Genetic Influences on Alcohol Use Behaviors

Overview

Journal medRxiv

Date 2024 Oct 14

PMID 39399022

Authors

Jeanne E Savage

Danielle M Dick

Danielle Posthuma

Affiliations

Soon will be listed here.

Abstract

Background: Genetic influences account for a substantial proportion of individual differences in alcohol use behaviors (AUBs). However, multiple distinct sets of genes are linked to different AUBs, which may explain their dramatic variability in risk factors and manifestations. In this study, we explore whether intermediate neurobiological traits and alcohol-related cognitions mediate the relationship between polygenic scores (PGS) and multiple AUBs, with the aim to better understand processes captured by different genetic profiles.

Methods: Using results from prior genome-wide association studies, we derived PGS for 6 AUBs in participants from Spit for Science, a longitudinal study of college students in the U.S. (n=4,549). Self-report measures included personality traits, alcohol expectancies, drinking motivations, and alcohol sensitivity measures as well as drinking frequency, drinking quantity, alcohol use disorder (AUD) symptoms, and maximum drinks in 24 hours. Using linear regression and multiple mediation models, we investigated the direct and indirect effects of PGS on AUBs.

Results: In univariable regression results, PGSs indexing broad AUB dimensions such as drinks per week (DPW) and AUD predicted higher levels of sensation-seeking and multiple drinking motives, while PGSs (indexing a variable pattern of alcohol problems associated with a preference for beer) predicted higher negative urgency and lower alcohol sensitivity. Mediational models indicated strong direct and indirect effects of DPW PGSs on multiple AUBs via social/enhancement drinking motives and alcohol sensitivity, indirect effects of AUD PGSs on AUD symptoms via coping motives, and indirect effects of PGS on all AUBs via the joint effect of mediators including alcohol sensitivity.

Conclusions: These findings provide initial evidence that the genetic influences on different AUBs are associated with and partially mediated by intermediate neurobiological and cognitive factors, which may be more amenable to intervention. Greater focus on drinking motives and alcohol sensitivity is warranted in genetic research, as well as attention to the heterogeneous pathways linking genes to alcohol use outcomes.

References

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

Dick D, Meyers J, Rose R, Kaprio J, Kendler K . Measures of current alcohol consumption and problems: two independent twin studies suggest a complex genetic architecture. Alcohol Clin Exp Res. 2011; 35(12):2152-61. PMC: 3215847. DOI: 10.1111/j.1530-0277.2011.01564.x. View

Salvatore J, Aliev F, Edwards A, Evans D, Macleod J, Hickman M . Polygenic scores predict alcohol problems in an independent sample and show moderation by the environment. Genes (Basel). 2014; 5(2):330-46. PMC: 4094936. DOI: 10.3390/genes5020330. View

Salvatore J, Thomas N, Cho S, Adkins A, Kendler K, Dick D . The role of romantic relationship status in pathways of risk for emerging adult alcohol use. Psychol Addict Behav. 2016; 30(3):335-44. PMC: 4880412. DOI: 10.1037/adb0000145. View

Strom H, Adolfsen F, Fossum S, Kaiser S, Martinussen M . Effectiveness of school-based preventive interventions on adolescent alcohol use: a meta-analysis of randomized controlled trials. Subst Abuse Treat Prev Policy. 2014; 9:48. PMC: 4274678. DOI: 10.1186/1747-597X-9-48. View

Bresin K, Mekawi Y . The "Why" of Drinking Matters: A Meta-Analysis of the Association Between Drinking Motives and Drinking Outcomes. Alcohol Clin Exp Res. 2020; 45(1):38-50. DOI: 10.1111/acer.14518. View

Lewis C, Vassos E . Polygenic risk scores: from research tools to clinical instruments. Genome Med. 2020; 12(1):44. PMC: 7236300. DOI: 10.1186/s13073-020-00742-5. View

Litten R, Ryan M, Falk D, Reilly M, Fertig J, Koob G . Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res. 2015; 39(4):579-84. DOI: 10.1111/acer.12669. View

Connor K, Davidson J . Development of a new resilience scale: the Connor-Davidson Resilience Scale (CD-RISC). Depress Anxiety. 2003; 18(2):76-82. DOI: 10.1002/da.10113. View

10.

Zhou H, Kember R, Deak J, Xu H, Toikumo S, Yuan K . Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals. Nat Med. 2023; 29(12):3184-3192. PMC: 10719093. DOI: 10.1038/s41591-023-02653-5. View

11.

Lai D, Wetherill L, Kapoor M, Johnson E, Schwandt M, Ramchandani V . Genome-wide association studies of the self-rating of effects of ethanol (SRE). Addict Biol. 2019; 25(2):e12800. PMC: 6940552. DOI: 10.1111/adb.12800. View

12.

Peterson R, Edwards A, Bacanu S, Dick D, Kendler K, Webb B . The utility of empirically assigning ancestry groups in cross-population genetic studies of addiction. Am J Addict. 2017; 26(5):494-501. PMC: 5646819. DOI: 10.1111/ajad.12586. View

13.

Prescott C, Cross R, Kuhn J, Horn J, Kendler K . Is risk for alcoholism mediated by individual differences in drinking motivations?. Alcohol Clin Exp Res. 2004; 28(1):29-39. DOI: 10.1097/01.ALC.0000106302.75766.F0. View

14.

Mallard T, Savage J, Johnson E, Huang Y, Edwards A, Hottenga J . Item-Level Genome-Wide Association Study of the Alcohol Use Disorders Identification Test in Three Population-Based Cohorts. Am J Psychiatry. 2021; 179(1):58-70. PMC: 9272895. DOI: 10.1176/appi.ajp.2020.20091390. View

15.

Sieri S, Agudo A, Kesse E, Klipstein-Grobusch K, San-Jose B, Welch A . Patterns of alcohol consumption in 10 European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) project. Public Health Nutr. 2003; 5(6B):1287-96. DOI: 10.1079/PHN2002405. View

16.

Whelan R, Watts R, Orr C, Althoff R, Artiges E, Banaschewski T . Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature. 2014; 512(7513):185-9. PMC: 4486207. DOI: 10.1038/nature13402. View

17.

Poore H, Hatoum A, Mallard T, Sanchez-Roige S, Waldman I, Palmer A . A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders. Addict Biol. 2023; 28(9):e13319. PMC: 11010459. DOI: 10.1111/adb.13319. View

18.

Chang C, Chow C, Tellier L, Vattikuti S, Purcell S, Lee J . Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015; 4:7. PMC: 4342193. DOI: 10.1186/s13742-015-0047-8. View

19.

Kendler K, Ohlsson H, Edwards A, Sundquist J, Sundquist K . Mediational Pathways From Genetic Risk to Alcohol Use Disorder in Swedish Men and Women. J Stud Alcohol Drugs. 2021; 82(3):431-438. PMC: 8328233. View

20.

Savage J, Dick D . Drinking Motives, Alcohol Misuse, and Internalizing and Externalizing Psychopathology across College: A Cross-Lagged Panel Study. Subst Use Misuse. 2023; 58(11):1377-1387. PMC: 11141776. DOI: 10.1080/10826084.2023.2223269. View