{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T04:11:52Z","timestamp":1780632712666,"version":"3.54.1"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K99HL156052"],"award-info":[{"award-number":["K99HL156052"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"crossref","award":["Undergraduate Translational Research Immersion Program"],"award-info":[{"award-number":["Undergraduate Translational Research Immersion Program"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006920","name":"University of Pennsylvania","doi-asserted-by":"crossref","award":["Undergraduate Research Mentoring Program"],"award-info":[{"award-number":["Undergraduate Research Mentoring Program"]}],"id":[{"id":"10.13039\/100006920","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Genome wide association studies (GWAS) have associated thousands of loci with quantitative human blood trait variation. Loci and related genes that impact blood trait variation may regulate blood cell-intrinsic biological processes, or alternatively impact blood cell development and function via systemic factors. Clinical observations have linked tobacco or alcohol use with altered blood traits, but these trait relationships have not been systematically explored at the genetic level. Applying a Mendelian randomization (MR) framework to GWAS summary statistics, we explore relationships between smoking and drinking behaviors with 15 quantitative blood traits. We find that the effects of smoking and drinking are confined to red blood cell traits. An instrumental variable (IV) comprised of 113 single nucleotide polymorphisms (SNPs) associated with smoking initiation is associated with decreased hemoglobin (HGB: Effect = -0.07 standard deviation units [95% confidence interval = -0.03 to -0.10 SD units], P = 1x10\n                    <jats:sup>-4<\/jats:sup>\n                    ), hematocrit (HCT: Effect = -0.06 [-0.03 - -0.09] SD units, P = 4x10\n                    <jats:sup>-4<\/jats:sup>\n                    ), and red blood cell count (RBC: Effect = -0.05 [-0.02 - -0.09] SD units, P = 5x10\n                    <jats:sup>-3<\/jats:sup>\n                    ) without impacting platelet count (P = 0.9) or white blood cell count (P = 0.6). Similarly, an IV associated with an increased number of alcoholic drinks consumed per week is associated with decreased HGB (Effect = -0.22 [-0.42 - -0.02] SD units, P = 3x10\n                    <jats:sup>-2<\/jats:sup>\n                    ) and RBC (Effect = -0.27 [-0.51 - -0.03] SD units, P = 3x10\n                    <jats:sup>-2<\/jats:sup>\n                    ). Using multivariable MR and causal mediation analyses, we find that an increased genetic predisposition to smoking initiation is associated with increased alcohol intake, and that alcohol use mediates the genetic effect of smoking initiation on red blood cell traits. These findings demonstrate a novel role for genetically influenced behaviors on human blood traits, revealing opportunities to dissect related pathways and mechanisms that influence hematopoiesis and blood cell biology.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0309608","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T13:28:17Z","timestamp":1725542897000},"page":"e0309608","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetically influenced tobacco and alcohol use behaviors impact erythroid trait variation"],"prefix":"10.1371","volume":"19","author":[{"given":"Shriya","family":"Shivakumar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madison B.","family":"Wilken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Tsao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7676-9367","authenticated-orcid":true,"given":"B\u00e1rbara D.","family":"Bitarello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1830-9922","authenticated-orcid":true,"given":"Christopher S.","family":"Thom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"pone.0309608.ref001","unstructured":"U.S. CDC. United States Center for Disease Control. In: https:\/\/www.cdc.gov\/tobacco\/data_statistics\/fact_sheets\/adult_data\/cig_smoking\/index.htm. 21 Apr 2022."},{"key":"pone.0309608.ref002","unstructured":"U.S. NIAAA. United States National Institute on Alcohol Abuse and Alcoholism. In: https:\/\/www.niaaa.nih.gov\/sites\/default\/files\/publications\/NIAAA_Alcohol_FactsandStats_102020_0.pdf. 21 Apr 2022."},{"key":"pone.0309608.ref003","doi-asserted-by":"crossref","first-page":"E223849","DOI":"10.1001\/jamanetworkopen.2022.3849","article-title":"Association of Habitual Alcohol Intake with Risk of Cardiovascular Disease.","volume":"5","author":"KJ Biddinger","year":"2022","journal-title":"JAMA Netw Open"},{"key":"pone.0309608.ref004","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMsa1211128","article-title":"21st-Century Hazards of Smoking and Benefits of Cessation in the United States","volume":"368","author":"P Jha","year":"2013","journal-title":"New England Journal of Medicine"},{"key":"pone.0309608.ref005","first-page":"e-1","article-title":"Alcohol\u2019s effects on the cardiovascular system","volume":"38","author":"MR Piano","year":"2017","journal-title":"Alcohol Res"},{"key":"pone.0309608.ref006","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1161\/ATVBAHA.112.300154","article-title":"Mechanisms of coronary thrombosis in cigarette smoke exposure","volume":"33","author":"RS Barua","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"pone.0309608.ref007","article-title":"Crosstalk between red blood cells and the immune system and its impact on atherosclerosis","author":"B Buttari","year":"2015","journal-title":"BioMed Research International. Hindawi Publishing Corporation"},{"key":"pone.0309608.ref008","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s12920-020-00742-9","article-title":"Genetic colocalization atlas points to common regulatory sites and genes for hematopoietic traits and hematopoietic contributions to disease phenotypes","volume":"13","author":"C Thom","year":"2020","journal-title":"BMC Med Genomics"},{"key":"pone.0309608.ref009","doi-asserted-by":"crossref","first-page":"132","DOI":"10.5455\/medarh.2017.71.132-136","article-title":"Effect of Cigarette Smoking on Haematological Parameters in Healthy Population.","volume":"71","author":"M Malenica","year":"2017","journal-title":"Med Arch."},{"key":"pone.0309608.ref010","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/oxfordjournals.aje.a008997","article-title":"Longitudinal relation between smoking and white blood cells","volume":"144","author":"J Sunyer","year":"1996","journal-title":"Am J Epidemiol"},{"key":"pone.0309608.ref011","first-page":"116","article-title":"Effects of cigarette smoke, nicotine and cotinine on red blood cell hemolysis and their -SH capacity","volume":"10","author":"S Asgary","year":"2005","journal-title":"Exp Clin Cardiol"},{"key":"pone.0309608.ref012","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1001\/jama.1990.03450120068031","article-title":"The Effect of Cigarette Smoking on Hemoglobin Levels and Anemia Screening. JAMA","volume":"264","author":"D Nordenberg","year":"1990","journal-title":"The Journal of the American Medical Association"},{"key":"pone.0309608.ref013","first-page":"42","article-title":"The Hematological Complications of Alcoholism.","volume":"21","author":"HS Ballard","year":"1997","journal-title":"Alcohol Health Res World"},{"key":"pone.0309608.ref014","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1751-553X.2008.01067.x","article-title":"Anaemia and cigarette smoking.","volume":"30","author":"JA Leifert","year":"2008","journal-title":"Int J Lab Hematol"},{"key":"pone.0309608.ref015","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.cell.2020.06.045","article-title":"Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.","volume":"182","author":"MH Chen","year":"2020","journal-title":"Cell"},{"key":"pone.0309608.ref016","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.cell.2020.08.008","article-title":"The Polygenic and Monogenic Basis of Blood Traits and Diseases","volume":"182","author":"D Vuckovic","year":"2020","journal-title":"Cell"},{"key":"pone.0309608.ref017","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.cell.2016.10.042","article-title":"The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease","volume":"167","author":"WJ Astle","year":"2016","journal-title":"Cell"},{"key":"pone.0309608.ref018","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 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randomization studies.","volume":"40","author":"S Burgess","year":"2011","journal-title":"Int J Epidemiol."},{"key":"pone.0309608.ref023","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/gepi.21998","article-title":"Bias due to participant overlap in two-sample Mendelian randomization","volume":"40","author":"S Burgess","year":"2016","journal-title":"Genet Epidemiol"},{"key":"pone.0309608.ref024","first-page":"1","article-title":"Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study.","author":"RE Wootton","year":"2019","journal-title":"Psychol Med."},{"key":"pone.0309608.ref025","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1093\/hmg\/ddaa193","article-title":"Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes but not coronary artery disease","volume":"29","author":"CS Thom","year":"2020","journal-title":"Hum Mol Genet"},{"key":"pone.0309608.ref026","doi-asserted-by":"crossref","first-page":"e75317","DOI":"10.7554\/eLife.75317","article-title":"Body mass index and adipose distribution have opposing genetic impacts on human blood traits","volume":"11","author":"C Thom","year":"2022","journal-title":"Elife"},{"key":"pone.0309608.ref027","first-page":"20","article-title":"Alcoholism and Co-Occurring Disorders.","author":"S Shiffman","year":"1996","journal-title":"Alcohol Health Res World"},{"key":"pone.0309608.ref028","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/j.cell.2021.01.049","article-title":"Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis","volume":"184","author":"A Heyde","year":"2021","journal-title":"Cell"},{"key":"pone.0309608.ref029","article-title":"Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease","author":"D Rohde","year":"2021","journal-title":"Nature Cardiovascular Research"},{"key":"pone.0309608.ref030","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"},{"key":"pone.0309608.ref031","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/hmg\/ddy327","article-title":"Meta-Analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry","volume":"28","author":"SL Pulit","year":"2019","journal-title":"Hum Mol Genet"},{"key":"pone.0309608.ref032","article-title":"Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis","author":"M Vujkovic","year":"2020","journal-title":"Nat Genet"},{"key":"pone.0309608.ref033","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","article-title":"Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease","volume":"122","author":"P Van Der Harst","year":"2018","journal-title":"Circ Res"},{"key":"pone.0309608.ref034","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41588-023-01596-4","article-title":"Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference","volume":"56","author":"X Meng","year":"2024","journal-title":"Nat Genet"},{"key":"pone.0309608.ref035","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/s41588-020-00757-z","article-title":"Genetics of 35 blood and urine biomarkers in the UK Biobank","volume":"53","author":"N Sinnott-Armstrong","year":"2021","journal-title":"Nat 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R: A language and environment for statistical computing. Vienna, Austria. URL https:\/\/www.R-project.org\/. Vienna, Austria: R Foundation for Statistical Computing; 2021."},{"key":"pone.0309608.ref038","doi-asserted-by":"crossref","first-page":"e34408","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":"pone.0309608.ref039","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"},{"key":"pone.0309608.ref040","doi-asserted-by":"crossref","first-page":"e1007081","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data.","volume":"13","author":"G Hemani","year":"2017","journal-title":"PLoS Genet."},{"key":"pone.0309608.ref041","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1534\/genetics.117.300191","article-title":"Dissecting causal pathways using mendelian randomization with summarized genetic data: Application to age at menarche and risk of breast cancer","volume":"207","author":"S Burgess","year":"2017","journal-title":"Genetics"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0309608","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T13:28:51Z","timestamp":1725542931000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0309608"}},"subtitle":[],"editor":[{"given":"J. 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