{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:32:22Z","timestamp":1767177142906,"version":"build-2238731810"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011824","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000}}],"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["218495\/Z\/19\/Z"],"award-info":[{"award-number":["218495\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>The alcohol harm paradox, whereby low socioeconomic position (SEP) groups experience greater alcohol-related harms at a given level of alcohol consumption, is not yet fully understood. In observational studies, key drivers are correlated and share similar confounding structures. We used multivariable Mendelian randomization (MVMR) to estimate the direct causal effect of alcohol (drinks per week) and education (years of schooling) on multiple health outcomes, accounting for the effect of the other. Previously published genome-wide association summary (GWAS) statistics for drinks per week and years of schooling were used, and outcome summary statistics were generated from individual-level data from UK Biobank (N\u2009=\u2009462,818). Inverse variance weighted analyses demonstrated evidence for direct effects of alcohol and education on liver diseases (alcoholic liver disease: alcohol OR = 50.19, 95% CI 19.35 to 130.21 and education OR = 0.27, 95% CI 0.14 to 0.53; other liver diseases: alcohol OR = 1.82, 95% CI 1.12 to 2.94 and education OR = 0.42, 95% CI 0.30 to 0.58), mental and behavioural disorders due to alcohol (alcohol OR = 12.89, 95% CI 7.46 to 22.27 and education OR = 0.51, 95% CI 0.35 to 0.75), and stroke (alcohol OR = 1.94, 95% CI 1.30 to 2.89 and education OR = 0.73, 95% CI 0.55 to 0.97). There was evidence for direct effects of education on depression, anxiety, influenza\/pneumonia, and heart disease. In contrast, there was evidence of total (without considering the effect of education), but not direct, effects of alcohol on depression, influenza\/pneumonia, epilepsy, and injuries. Although caution is required when interpreting these results, given weak instruments for alcohol, these results provide some evidence that the alcohol harm paradox is partially due to the protective effect of additional years of education. Replication with strong genetic instruments for drinks per week would be necessary to draw causal inferences.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011824","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T19:55:18Z","timestamp":1755201318000},"page":"e1011824","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Understanding the alcohol harm paradox: A multivariable mendelian randomization approach"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1185-5744","authenticated-orcid":true,"given":"Gemma","family":"Sawyer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Sallis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"Munaf\u00f2","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-6595","authenticated-orcid":true,"given":"Liam","family":"Mahedy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7944-2981","authenticated-orcid":true,"given":"Jasmine","family":"Khouja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"pgen.1011824.ref001","unstructured":"World Health Organization. Alcohol. 2018 [cited 9 Mar 2022]. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/alcohol"},{"key":"pgen.1011824.ref002","unstructured":"Smith K, Foster Alcohol J. Health Inequalities and the Harm Paradox: Why some groups face greater problems despite consuming less alcohol. 2014. https:\/\/www.alcoholpolicy.net\/2014\/11\/alcohol-health-inequalities-and-the-harm-paradox-ias-report-reviews-higher-harms-in-deprived-groups.html"},{"key":"pgen.1011824.ref003","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12889-016-2766-x","article-title":"The alcohol harm paradox: using a national survey to explore how alcohol may disproportionately impact health in deprived individuals","volume":"16","author":"MA Bellis","year":"2016","journal-title":"BMC Public Health"},{"issue":"9","key":"pgen.1011824.ref004","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0160666","article-title":"Deconstructing the Alcohol Harm Paradox: A Population Based Survey of Adults in England","volume":"11","author":"E Beard","year":"2016","journal-title":"PLoS One"},{"issue":"9","key":"pgen.1011824.ref005","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1136\/jech-2018-211634","article-title":"Socioeconomic position and alcohol-related harm in Danish adolescents","volume":"73","author":"SP M\u00f8ller","year":"2019","journal-title":"J Epidemiol Community Health"},{"key":"pgen.1011824.ref006","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1186\/s12889-016-3265-9","article-title":"Unravelling the alcohol harm paradox: a population-based study of social gradients across very heavy drinking thresholds","volume":"16","author":"D Lewer","year":"2016","journal-title":"BMC Public Health"},{"issue":"5","key":"pgen.1011824.ref007","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1111\/add.13726","article-title":"Understanding the alcohol harm paradox: an analysis of sex- and condition-specific hospital admissions by socio-economic group for alcohol-associated conditions in England","volume":"112","author":"S Sadler","year":"2017","journal-title":"Addiction"},{"issue":"10082","key":"pgen.1011824.ref008","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1016\/S0140-6736(17)30819-X","article-title":"Smoking prevalence and attributable disease burden in 195 countries and territories, 1990-2015: a systematic analysis from the Global Burden of Disease Study 2015","volume":"389","author":"GBD 2015 Tobacco Collaborators","year":"2017","journal-title":"Lancet"},{"issue":"1","key":"pgen.1011824.ref009","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1186\/s12889-019-8015-3","article-title":"Drinking beer, wine or spirits - does it matter for inequalities in alcohol-related hospital admission? A record-linked longitudinal study in Wales","volume":"19","author":"A Gartner","year":"2019","journal-title":"BMC Public Health"},{"issue":"8","key":"pgen.1011824.ref010","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1111\/add.15395","article-title":"Joint effects of alcohol use, smoking and body mass index as an explanation for the alcohol harm paradox: causal mediation analysis of eight cohort studies","volume":"116","author":"S Pe\u00f1a","year":"2021","journal-title":"Addiction"},{"issue":"1","key":"pgen.1011824.ref011","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"\u201cMendelian randomization\u201d: can genetic epidemiology contribute to understanding environmental determinants of disease?","volume":"32","author":"GD Smith","year":"2003","journal-title":"Int J Epidemiol"},{"issue":"3","key":"pgen.1011824.ref012","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"E Sanderson","year":"2019","journal-title":"Int J Epidemiol"},{"key":"pgen.1011824.ref013","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s43586-021-00092-5","article-title":"Mendelian randomization","volume":"2","author":"E Sanderson","year":"2022","journal-title":"Nat Rev Methods Primers"},{"issue":"16","key":"pgen.1011824.ref014","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement","volume":"326","author":"VW Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"pgen.1011824.ref015","doi-asserted-by":"crossref","unstructured":"Von Elm E, Altman DG, Egger M, Pocock SJ, G\u00f8tzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. 2007. www.thelancet.comwww.plosmedicine.org","DOI":"10.1371\/journal.pmed.0040296"},{"issue":"2","key":"pgen.1011824.ref016","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41588-018-0307-5","article-title":"Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use","volume":"51","author":"M Liu","year":"2019","journal-title":"Nat Genet"},{"issue":"7604","key":"pgen.1011824.ref017","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/nature17671","article-title":"Genome-wide association study identifies 74 loci associated with educational attainment","volume":"533","author":"A Okbay","year":"2016","journal-title":"Nature"},{"issue":"4","key":"pgen.1011824.ref018","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/s41380-019-0535-9","article-title":"Educational attainment impacts drinking behaviors and risk for alcohol dependence: results from a two-sample Mendelian randomization study with ~780,000 participants","volume":"26","author":"DB Rosoff","year":"2021","journal-title":"Mol Psychiatry"},{"key":"pgen.1011824.ref019","unstructured":"UNESCO. International Standard Classification of Education ISCED 1997. 2006. https:\/\/isced.uis.unesco.org\/wp-content\/uploads\/sites\/15\/2022\/12\/international-standard-classification-of-education-1997-en_0.pdf"},{"issue":"3","key":"pgen.1011824.ref020","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age","volume":"12","author":"C Sudlow","year":"2015","journal-title":"PLoS Med"},{"key":"pgen.1011824.ref021","unstructured":"Mitchell R, Elsworth B, Raistrick C, Paternoster L, Hemani G, Gaunt T. MRC IEU UK Biobank GWAS pipeline version 2. 2019. https:\/\/doi.org\/10.5523\/bris.pnoat8cxo0u52p6ynfaekeigi"},{"key":"pgen.1011824.ref022","unstructured":"Public Health England and UK Health Forum. Alcohol-attributable fractions for England: An update. In: GOV.UK [Internet]. 12 Jun 2020 [cited 8 Nov 2022]. https:\/\/www.gov.uk\/government\/publications\/alcohol-attributable-fractions-for-england-an-update"},{"key":"pgen.1011824.ref023","unstructured":"World Health Organization. Global status report on alcohol and health 2018. 2018. https:\/\/www.who.int\/publications\/i\/item\/9789241565639"},{"key":"pgen.1011824.ref024","unstructured":"Jones L, Dedman D, Tocque K. Alcohol-Attributable Fractions for England: Alcohol-Attributable Mortality and Hospital Admissions Systematic review of interventions to enhance health service contacts with parents and infants View project. 2008. https:\/\/www.researchgate.net\/publication\/235428834"},{"key":"pgen.1011824.ref025","unstructured":"R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2021 [cited 18 Mar 2022]. https:\/\/www.R-project.org\/"},{"issue":"6","key":"pgen.1011824.ref026","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1093\/ije\/dyx034","article-title":"MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data","volume":"46","author":"OO Yavorska","year":"2017","journal-title":"Int J Epidemiol"},{"key":"pgen.1011824.ref027","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.34408","article-title":"The MR-Base platform supports systematic causal inference across the human phenome","volume":"7","author":"G Hemani","year":"2018","journal-title":"Elife"},{"key":"pgen.1011824.ref028","unstructured":"Spiller W, Bowden J, Sanderson E. MVMR: MVMR. R package version 0.3. 2022. https:\/\/github.com\/WSpiller\/MVMR"},{"issue":"5","key":"pgen.1011824.ref029","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"M Verbanck","year":"2018","journal-title":"Nat Genet"},{"issue":"4","key":"pgen.1011824.ref030","doi-asserted-by":"crossref","DOI":"10.1002\/alz.70109","article-title":"Addressing overfitting bias due to sample overlap in polygenic risk scoring","volume":"21","author":"S Jeong","year":"2025","journal-title":"Alzheimers Dement"},{"issue":"25","key":"pgen.1011824.ref031","doi-asserted-by":"crossref","first-page":"5434","DOI":"10.1002\/sim.9133","article-title":"Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization","volume":"40","author":"E Sanderson","year":"2021","journal-title":"Stat Med"},{"issue":"7","key":"pgen.1011824.ref032","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/gepi.21758","article-title":"Mendelian randomization analysis with multiple genetic variants using summarized data","volume":"37","author":"S Burgess","year":"2013","journal-title":"Genet Epidemiol"},{"issue":"2","key":"pgen.1011824.ref033","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression","volume":"44","author":"J Bowden","year":"2015","journal-title":"Int J Epidemiol"},{"issue":"4","key":"pgen.1011824.ref034","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1002\/gepi.21965","article-title":"Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator","volume":"40","author":"J Bowden","year":"2016","journal-title":"Genet Epidemiol"},{"issue":"6","key":"pgen.1011824.ref035","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"FP Hartwig","year":"2017","journal-title":"Int J Epidemiol"},{"key":"pgen.1011824.ref036","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.g4164","article-title":"Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data","volume":"349","author":"MV Holmes","year":"2014","journal-title":"BMJ"},{"issue":"7","key":"pgen.1011824.ref037","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41593-020-0643-5","article-title":"Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits","volume":"23","author":"H Zhou","year":"2020","journal-title":"Nat Neurosci"},{"issue":"6","key":"pgen.1011824.ref038","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1093\/ije\/dyad104","article-title":"The causal effects of education on adult health, mortality and income: evidence from Mendelian randomization and the raising of the school leaving age","volume":"52","author":"NM Davies","year":"2023","journal-title":"Int J Epidemiol"},{"issue":"2","key":"pgen.1011824.ref039","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41562-017-0279-y","article-title":"The Causal Effects of Education on Health Outcomes in the UK Biobank","volume":"2","author":"NM Davies","year":"2018","journal-title":"Nat Hum Behav"},{"issue":"6","key":"pgen.1011824.ref040","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.socscimed.2007.12.019","article-title":"Does a higher educational level protect against anxiety and depression? The HUNT study","volume":"66","author":"I Bjelland","year":"2008","journal-title":"Soc Sci Med"},{"key":"pgen.1011824.ref041","article-title":"Education and coronary heart disease: mendelian randomisation study","volume":"358","author":"T Tillmann","year":"2017","journal-title":"BMJ"},{"issue":"3","key":"pgen.1011824.ref042","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1017\/S0033291719000357","article-title":"Potential influence of socioeconomic status on genetic correlations between alcohol consumption measures and mental health","volume":"50","author":"AT Marees","year":"2020","journal-title":"Psychol Med"},{"issue":"7941","key":"pgen.1011824.ref043","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41586-022-05477-4","article-title":"Genetic diversity fuels gene discovery for tobacco and alcohol use","volume":"612","author":"GRB Saunders","year":"2022","journal-title":"Nature"},{"issue":"3","key":"pgen.1011824.ref044","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcac125","article-title":"Genome-wide association studies for Alzheimer\u2019s disease: bigger is not always better","volume":"4","author":"V Escott-Price","year":"2022","journal-title":"Brain Commun"},{"issue":"1","key":"pgen.1011824.ref045","doi-asserted-by":"crossref","first-page":"25321","DOI":"10.1038\/s41598-024-73333-8","article-title":"Impact of Alcohol Consumption on Lifespan: a Mendelian randomization study in Europeans","volume":"14","author":"ZL Jiesisibieke","year":"2024","journal-title":"Sci Rep"},{"key":"pgen.1011824.ref046","volume-title":"Weak instruments in multivariable Mendelian randomization: methods and practice","author":"A Patel","year":"2024"},{"issue":"12","key":"pgen.1011824.ref047","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1038\/s41591-023-02653-5","article-title":"Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals","volume":"29","author":"H Zhou","year":"2023","journal-title":"Nat Med"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1011824","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T00:00:00Z","timestamp":1755734400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011824","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:58:30Z","timestamp":1755799110000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1011824"}},"subtitle":[],"editor":[{"given":"Renato","family":"Polimanti","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,8,14]]},"references-count":47,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1011824","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,14]]}}}