{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:35:46Z","timestamp":1793262946842,"version":"4.5.0"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T00:00:00Z","timestamp":1710201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Med"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Substance use behaviours (SUB) including smoking, alcohol consumption, and coffee intake are associated with many health outcomes. However, whether the health effects of SUB are causal remains controversial, especially for alcohol consumption and coffee intake.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In this study, we assess 11 commonly used Mendelian Randomization (MR) methods by simulation and apply them to investigate the causal relationship between 7 SUB traits and health outcomes. We also combine stratified regression, genetic correlation, and MR analyses to investigate the dosage-dependent effects.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We show that smoking initiation has widespread risk effects on common diseases such as asthma, type 2 diabetes, and peripheral vascular disease. Alcohol consumption shows risk effects specifically on cardiovascular diseases, dyslipidemia, and hypertensive diseases. We find evidence of dosage-dependent effects of coffee and tea intake on common diseases (e.g., cardiovascular disease and osteoarthritis). We observe that the minor allele effect of rs4410790 (the top signal for tea intake level) is negative on heavy tea intake\n \n \n $$({\\hat{b}}_{GWAS}=-0.091,s.e.=0.007,P=4.90\\times {10}^{-35})$$<\/jats:tex-math>\n \n \n (<\/mml:mo>\n \n \n \n \n \n b<\/mml:mi>\n <\/mml:mrow>\n \n \u0302<\/mml:mo>\n <\/mml:mrow>\n <\/mml:mover>\n <\/mml:mrow>\n \n G<\/mml:mi>\n W<\/mml:mi>\n A<\/mml:mi>\n S<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msub>\n =<\/mml:mo>\n \u2212<\/mml:mo>\n 0.091<\/mml:mn>\n ,<\/mml:mo>\n s<\/mml:mi>\n .<\/mml:mo>\n e<\/mml:mi>\n .<\/mml:mo>\n =<\/mml:mo>\n 0.007<\/mml:mn>\n ,<\/mml:mo>\n P<\/mml:mi>\n =<\/mml:mo>\n 4.90<\/mml:mn>\n \u00d7<\/mml:mo>\n \n \n 10<\/mml:mn>\n <\/mml:mrow>\n \n \u2212<\/mml:mo>\n 35<\/mml:mn>\n <\/mml:mrow>\n <\/mml:msup>\n <\/mml:mrow>\n )<\/mml:mo>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n <\/jats:p>\n \n but positive on moderate tea intake\n \n \n $$({\\hat{b}}_{GWAS}=0.034,s.e.=0.006,P=3.40\\times {10}^{-8})$$<\/jats:tex-math>\n \n \n (<\/mml:mo>\n \n \n \n \n \n b<\/mml:mi>\n <\/mml:mrow>\n \n \u0302<\/mml:mo>\n <\/mml:mrow>\n <\/mml:mover>\n <\/mml:mrow>\n \n G<\/mml:mi>\n W<\/mml:mi>\n A<\/mml:mi>\n S<\/mml:mi>\n <\/mml:mrow>\n <\/mml:msub>\n =<\/mml:mo>\n 0.034<\/mml:mn>\n ,<\/mml:mo>\n s<\/mml:mi>\n .<\/mml:mo>\n e<\/mml:mi>\n .<\/mml:mo>\n =<\/mml:mo>\n 0.006<\/mml:mn>\n ,<\/mml:mo>\n P<\/mml:mi>\n =<\/mml:mo>\n 3.40<\/mml:mn>\n \u00d7<\/mml:mo>\n \n \n 10<\/mml:mn>\n <\/mml:mrow>\n \n \u2212<\/mml:mo>\n 8<\/mml:mn>\n <\/mml:mrow>\n <\/mml:msup>\n <\/mml:mrow>\n )<\/mml:mo>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n , compared to the non-tea-drinkers.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our study reveals the complexity of the health effects of SUB and informs design for future studies aiming to dissect the causal relationships between behavioural traits and complex diseases.<\/jats:p>\n <\/jats:sec>","DOI":"10.1038\/s43856-024-00473-3","type":"journal-article","created":{"date-parts":[[2024,3,12]],"date-time":"2024-03-12T20:02:14Z","timestamp":1710273734000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Unravelling the complex causal effects of substance use behaviours on common diseases"],"prefix":"10.1038","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-0426","authenticated-orcid":false,"given":"Angli","family":"Xue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6783-3037","authenticated-orcid":false,"given":"Zhihong","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-3391","authenticated-orcid":false,"given":"Huanwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longda","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-8760","authenticated-orcid":false,"given":"Peter M.","family":"Visscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8801-5220","authenticated-orcid":false,"given":"Jian","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2001-2474","authenticated-orcid":false,"given":"Jian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,12]]},"reference":[{"key":"473_CR1","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1001\/archpsyc.58.9.810","volume":"58","author":"N Breslau","year":"2001","unstructured":"Breslau, N., Johnson, E. O., Hiripi, E. & Kessler, R. Nicotine dependence in the United States: prevalence, trends, and smoking persistence. Arch. Gen. Psychiatry 58, 810\u2013816 (2001).","journal-title":"Arch. Gen. Psychiatry"},{"key":"473_CR2","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1081\/JA-120024230","volume":"38","author":"M Adrian","year":"2003","unstructured":"Adrian, M. & Barry, S. J. Physical and mental health problems associated with the use of alcohol and drugs. Subs. Use Misuse 38, 1575\u20131614 (2003).","journal-title":"Subs. Use Misuse"},{"key":"473_CR3","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1093\/ije\/dyt173","volume":"43","author":"LT Wu","year":"2014","unstructured":"Wu, L. T. & Blazer, D. G. Substance use disorders and psychiatric comorbidity in mid and later life: a review. Int. J. Epidemiol. 43, 304\u2013317 (2014).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR4","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1001\/jama.2018.0900","volume":"319","author":"L Dwyer-Lindgren","year":"2018","unstructured":"Dwyer-Lindgren, L. et al. Trends and Patterns of Geographic Variation in Mortality From Substance Use Disorders and Intentional Injuries Among US Counties, 1980-2014. Jama-J. Am. Med. Asso. 319, 1013\u20131023 (2018).","journal-title":"Jama-J. Am. Med. Asso."},{"key":"473_CR5","unstructured":"Organization, W. H. WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco, (World Health Organization, 2011)."},{"key":"473_CR6","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/S0140-6736(13)60355-4","volume":"381","author":"CJ Murray","year":"2013","unstructured":"Murray, C. J. et al. UK health performance: findings of the Global Burden of Disease Study 2010. Lancet 381, 997\u20131020 (2013).","journal-title":"Lancet"},{"key":"473_CR7","unstructured":"Organization, W. H. Global status report on alcohol and health 2018, (World Health Organization, 2019)."},{"key":"473_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00213-004-2000-x","volume":"176","author":"LM Juliano","year":"2004","unstructured":"Juliano, L. M. & Griffiths, R. R. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl) 176, 1\u201329 (2004).","journal-title":"Psychopharmacology (Berl)"},{"key":"473_CR9","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1080\/10408390903586412","volume":"51","author":"MS Butt","year":"2011","unstructured":"Butt, M. S. & Sultan, M. T. Coffee and its consumption: benefits and risks. Crit. Rev. Food Sci. Nutr. 51, 363\u2013373 (2011).","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"473_CR10","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/S0140-6736(18)30134-X","volume":"391","author":"AM Wood","year":"2018","unstructured":"Wood, A. M. et al. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. Lancet 391, 1513\u20131523 (2018).","journal-title":"Lancet"},{"key":"473_CR11","doi-asserted-by":"crossref","unstructured":"Millwood, I. et al. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China. Lancet 393, 1831\u20131842 (2019).","DOI":"10.1016\/S0140-6736(18)31772-0"},{"key":"473_CR12","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1136\/bmj.2.4682.739","volume":"2","author":"R Doll","year":"1950","unstructured":"Doll, R. & Hill, A. B. Smoking and carcinoma of the lung; preliminary report. Br. Med. J. 2, 739\u2013748 (1950).","journal-title":"Br. Med. J."},{"key":"473_CR13","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1001\/jama.279.7.535","volume":"279","author":"SA Smith-Warner","year":"1998","unstructured":"Smith-Warner, S. A. et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 279, 535\u2013540 (1998).","journal-title":"JAMA"},{"key":"473_CR14","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1146\/annurev-genom-090314-050016","volume":"16","author":"DM Evans","year":"2015","unstructured":"Evans, D. M. & Davey Smith, G. Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality. Annu. Rev. Genomics Hum. Genet. 16, 327\u2013350 (2015).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"473_CR15","doi-asserted-by":"publisher","first-page":"k1767","DOI":"10.1136\/bmj.k1767","volume":"361","author":"R Carreras-Torres","year":"2018","unstructured":"Carreras-Torres, R. et al. Role of obesity in smoking behaviour: Mendelian randomisation study in UK Biobank. BMJ 361, k1767 (2018).","journal-title":"BMJ"},{"key":"473_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/srep18422","volume":"5","author":"Y Cho","year":"2015","unstructured":"Cho, Y. et al. Alcohol intake and cardiovascular risk factors: A Mendelian randomisation study. Sci. Rep. 5, 18422 (2015).","journal-title":"Sci. Rep."},{"key":"473_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/srep40653","volume":"7","author":"SH Gage","year":"2017","unstructured":"Gage, S. H. et al. Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization. Scientific Rep. 7, 40653 (2017).","journal-title":"Scientific Rep."},{"key":"473_CR18","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","volume":"44","author":"J Bowden","year":"2015","unstructured":"Bowden, J., Davey Smith, G. & Burgess, S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int. J. Epidemiol. 44, 512\u2013525 (2015).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR19","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1093\/ije\/dyx102","volume":"46","author":"FP Hartwig","year":"2017","unstructured":"Hartwig, F. P., Davey Smith, G. & Bowden, J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int. J. Epidemiol. 46, 1985\u20131998 (2017).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR20","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","volume":"50","author":"M Verbanck","year":"2018","unstructured":"Verbanck, M., Chen, C. Y., Neale, B. & Do, R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat. Genet. 50, 693\u2013698 (2018).","journal-title":"Nat. Genet."},{"key":"473_CR21","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","volume":"562","author":"C Bycroft","year":"2018","unstructured":"Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203\u2013209 (2018).","journal-title":"Nature"},{"key":"473_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02317-2","volume":"9","author":"Z Zhu","year":"2018","unstructured":"Zhu, Z. et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat. Commun. 9, 224 (2018).","journal-title":"Nat. Commun."},{"key":"473_CR23","unstructured":"Dabney, A., Storey, J. D. & Warnes, G. qvalue: Q-value estimation for false discovery rate control. R package version 1 (2010)."},{"key":"473_CR24","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1093\/ije\/dyr036","volume":"40","author":"S Burgess","year":"2011","unstructured":"Burgess, S. & Thompson, S. G., Collaboration, C.C.G. Avoiding bias from weak instruments in Mendelian randomization studies. Int. J. Epidemiol. 40, 755\u2013764 (2011).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR25","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1038\/mp.2017.153","volume":"22","author":"TK Clarke","year":"2017","unstructured":"Clarke, T. K. et al. Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117). Mol. Psychiatry 22, 1376\u20131384 (2017).","journal-title":"Mol. Psychiatry"},{"key":"473_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20237-6","volume":"12","author":"A Xue","year":"2021","unstructured":"Xue, A. et al. Genome-wide analyses of behavioural traits are subject to bias by misreports and longitudinal changes. Nat. Commun. 12, 20211 (2021).","journal-title":"Nat. Commun."},{"key":"473_CR27","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1038\/ng.3643","volume":"48","author":"S McCarthy","year":"2016","unstructured":"McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279\u20131283 (2016).","journal-title":"Nat. Genet."},{"key":"473_CR28","doi-asserted-by":"publisher","DOI":"10.1186\/s13742-015-0047-8","volume":"4","author":"CC Chang","year":"2015","unstructured":"Chang, C. C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).","journal-title":"Gigascience"},{"key":"473_CR29","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1038\/ng.3190","volume":"47","author":"PR Loh","year":"2015","unstructured":"Loh, P. R. et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat. Genet. 47, 284\u2013290 (2015).","journal-title":"Nat. Genet."},{"key":"473_CR30","doi-asserted-by":"crossref","unstructured":"Lloyd-Jones, L. R., Robinson, M. R., Yang, J. & Visscher, P. M. Transformation of Summary Statistics from Linear Mixed Model Association on All-or-None Traits to Odds Ratio. Genetics 208, 1397\u20131408 (2018).","DOI":"10.1534\/genetics.117.300360"},{"key":"473_CR31","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","volume":"50","author":"W Zhou","year":"2018","unstructured":"Zhou, W. et al. Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat. Genet. 50, 1335\u20131341 (2018).","journal-title":"Nat. Genet."},{"key":"473_CR32","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","volume":"53","author":"J Mbatchou","year":"2021","unstructured":"Mbatchou, J. et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nat. Genet. 53, 1097\u20131103 (2021).","journal-title":"Nat. Genet."},{"key":"473_CR33","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1038\/s41588-021-00954-4","volume":"53","author":"L Jiang","year":"2021","unstructured":"Jiang, L., Zheng, Z., Fang, H. & Yang, J. A generalized linear mixed model association tool for biobank-scale data. Nat. Genet. 53, 1616\u20131621 (2021).","journal-title":"Nat. Genet."},{"key":"473_CR34","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1161\/CIRCRESAHA.117.312086","volume":"122","author":"P van der Harst","year":"2018","unstructured":"van der Harst, P. & Verweij, N. Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease. Circ. Res. 122, 433\u2013443 (2018).","journal-title":"Circ. Res."},{"key":"473_CR35","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1038\/s41588-018-0241-6","volume":"50","author":"A Mahajan","year":"2018","unstructured":"Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505\u20131513 (2018).","journal-title":"Nat. Genet."},{"key":"473_CR36","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/ng.3359","volume":"47","author":"JZ Liu","year":"2015","unstructured":"Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979\u2013986 (2015).","journal-title":"Nat. Genet."},{"key":"473_CR37","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature12873","volume":"506","author":"Y Okada","year":"2014","unstructured":"Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376\u2013381 (2014).","journal-title":"Nature"},{"key":"473_CR38","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nature13595","volume":"511","author":"Schizophrenia Working Group of the Psychiatric Genomics, C.","year":"2014","unstructured":"Schizophrenia Working Group of the Psychiatric Genomics, C. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421\u2013427 (2014).","journal-title":"Nature"},{"key":"473_CR39","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1016\/j.cell.2018.05.046","volume":"173","author":"D Bipolar","year":"2018","unstructured":"Bipolar, D., Schizophrenia Working Group of the Psychiatric Genomics Consortium. Electronic address, d.r.v.e., Bipolar, D. & Schizophrenia Working Group of the Psychiatric Genomics, C. Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes. Cell 173, 1705\u20131715 e16 (2018).","journal-title":"Cell"},{"key":"473_CR40","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41588-018-0090-3","volume":"50","author":"NR Wray","year":"2018","unstructured":"Wray, N. R. et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat. Genet. 50, 668\u2013681 (2018).","journal-title":"Nat. Genet."},{"key":"473_CR41","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1038\/ng.2802","volume":"45","author":"JC Lambert","year":"2013","unstructured":"Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease. Nat. Genet. 45, 1452\u20131458 (2013).","journal-title":"Nat. Genet."},{"key":"473_CR42","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/ng.3826","volume":"49","author":"CM Phelan","year":"2017","unstructured":"Phelan, C. M. et al. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer. Nat. Genet. 49, 680\u2013691 (2017).","journal-title":"Nat. Genet."},{"key":"473_CR43","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/nature24284","volume":"551","author":"K Michailidou","year":"2017","unstructured":"Michailidou, K. et al. Association analysis identifies 65 new breast cancer risk loci. Nature 551, 92\u201394 (2017).","journal-title":"Nature"},{"key":"473_CR44","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/s41588-018-0330-6","volume":"51","author":"FR Schumacher","year":"2019","unstructured":"Schumacher, F. R. et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci (vol 50, pg 928, 2018). Nat. Genet. 51, 363\u2013363 (2019).","journal-title":"Nat. Genet."},{"key":"473_CR45","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1038\/ng.3406","volume":"47","author":"B Bulik-Sullivan","year":"2015","unstructured":"Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236\u20131241 (2015).","journal-title":"Nat. Genet."},{"key":"473_CR46","first-page":"100124","volume":"3","author":"J Sulc","year":"2022","unstructured":"Sulc, J., Sjaarda, J. & Kutalik, Z. Polynomial Mendelian randomization reveals non-linear causal effects for obesity-related traits. HGG Adv. 3, 100124 (2022).","journal-title":"HGG Adv."},{"key":"473_CR47","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","volume":"37","author":"S Burgess","year":"2013","unstructured":"Burgess, S., Butterworth, A. & Thompson, S. G. Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data. Genet. Epidemiol. 37, 658\u2013665 (2013).","journal-title":"Genet. Epidemiol."},{"key":"473_CR48","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gepi.21965","volume":"40","author":"J Bowden","year":"2016","unstructured":"Bowden, J., Smith, G. D., Haycock, P. C. & Burgess, S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet. Epidemiol. 40, 304\u2013314 (2016).","journal-title":"Genet. Epidemiol."},{"key":"473_CR49","unstructured":"Burgess, S., Bowden, J., Dudbridge, F. & Thompson, S. G. Robust instrumental variable methods using multiple candidate instruments with application to Mendelian randomization. arXiv preprint arXiv:1606.03729 (2016)."},{"key":"473_CR50","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/gepi.22295","volume":"44","author":"EAW Slob","year":"2020","unstructured":"Slob, E. A. W. & Burgess, S. A comparison of robust Mendelian randomization methods using summary data. Genet. Epidemiol. 44, 313\u2013329 (2020).","journal-title":"Genet. Epidemiol."},{"key":"473_CR51","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1214\/19-AOS1866","volume":"48","author":"Q Zhao","year":"2020","unstructured":"Zhao, Q., Wang, J., Hemani, G., Bowden, J. & Small, D. S. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Annal. Stat. 48, 1742\u20131769 (2020).","journal-title":"Annal. Stat."},{"key":"473_CR52","doi-asserted-by":"crossref","unstructured":"Qi, G. H. & Chatterjee, N. Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects. Nat. Commun. 10, 1941 (2019).","DOI":"10.1038\/s41467-019-09432-2"},{"key":"473_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14156-4","volume":"11","author":"S Burgess","year":"2020","unstructured":"Burgess, S., Foley, C. N., Allara, E., Staley, J. R. & Howson, J. M. M. A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat. Commun. 11, 376 (2020).","journal-title":"Nat. Commun."},{"key":"473_CR54","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1093\/ije\/dyw127","volume":"45","author":"DA Lawlor","year":"2016","unstructured":"Lawlor, D. A., Tilling, K. & Davey Smith, G. Triangulation in aetiological epidemiology. Int. J. Epidemiol. 45, 1866\u20131886 (2016).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR55","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1002\/gepi.22207","volume":"43","author":"JS Ong","year":"2019","unstructured":"Ong, J. S. & MacGregor, S. Implementing MR-PRESSO and GCTA-GSMR for pleiotropy assessment in Mendelian randomization studies from a practitioner\u2019s perspective. Genet. Epidemiol. 43, 609\u2013616 (2019).","journal-title":"Genet. Epidemiol."},{"key":"473_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-56014-9","volume":"9","author":"S Yuan","year":"2019","unstructured":"Yuan, S. & Larsson, S. C. A causal relationship between cigarette smoking and type 2 diabetes mellitus: A Mendelian randomization study. Scientific Rep. 9, 19342 (2019).","journal-title":"Scientific Rep."},{"key":"473_CR57","doi-asserted-by":"publisher","first-page":"3304","DOI":"10.1093\/eurheartj\/ehaa193","volume":"41","author":"SC Larsson","year":"2020","unstructured":"Larsson, S. C. et al. Genetic predisposition to smoking in relation to 14 cardiovascular diseases. Eur. Heart J. 41, 3304\u20133310 (2020).","journal-title":"Eur. Heart J."},{"key":"473_CR58","doi-asserted-by":"publisher","first-page":"e1003410","DOI":"10.1371\/journal.pmed.1003410","volume":"17","author":"DB Rosoff","year":"2020","unstructured":"Rosoff, D. B., Davey Smith, G., Mehta, N., Clarke, T.-K. & Lohoff, F. W. Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: a multivariable Mendelian randomization study. PLoS Med. 17, e1003410 (2020).","journal-title":"PLoS Med."},{"key":"473_CR59","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1038\/s41588-018-0307-5","volume":"51","author":"M Liu","year":"2019","unstructured":"Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237\u2013244 (2019).","journal-title":"Nat. Genet."},{"key":"473_CR60","doi-asserted-by":"publisher","first-page":"e0255801","DOI":"10.1371\/journal.pone.0255801","volume":"16","author":"J Lankester","year":"2021","unstructured":"Lankester, J., Zanetti, D., Ingelsson, E. & Assimes, T. L. Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study. PLoS One 16, e0255801 (2021).","journal-title":"PLoS One"},{"key":"473_CR61","first-page":"e002814","volume":"13","author":"SC Larsson","year":"2020","unstructured":"Larsson, S. C., Burgess, S., Mason, A. M. & Micha\u00eblsson, K. Alcohol consumption and cardiovascular disease: a Mendelian randomization study. Circulation: Genomic Prec. Med. 13, e002814 (2020).","journal-title":"Circulation: Genomic Prec. Med."},{"key":"473_CR62","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/S0140-6736(18)31310-2","volume":"392","author":"MG Griswold","year":"2018","unstructured":"Griswold, M. G. et al. Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 392, 1015\u20131035 (2018).","journal-title":"Lancet"},{"key":"473_CR63","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1046\/j.1360-0443.2000.951015056.x","volume":"95","author":"G Corrao","year":"2000","unstructured":"Corrao, G., Rubbiati, L., Bagnardi, V., Zambon, A. & Poikolainen, K. Alcohol and coronary heart disease: a meta-analysis. Addiction 95, 1505\u20131523 (2000).","journal-title":"Addiction"},{"key":"473_CR64","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1161\/CIRCULATIONAHA.108.832360","volume":"120","author":"L Djousse","year":"2009","unstructured":"Djousse, L., Lee, I. M., Buring, J. E. & Gaziano, J. M. Alcohol consumption and risk of cardiovascular disease and death in women: potential mediating mechanisms. Circulation 120, 237\u2013244 (2009).","journal-title":"Circulation"},{"key":"473_CR65","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1016\/S0140-6736(02)11436-X","volume":"360","author":"RM van Dam","year":"2002","unstructured":"van Dam, R. M. & Feskens, E. J. Coffee consumption and risk of type 2 diabetes mellitus. Lancet 360, 1477\u20131478 (2002).","journal-title":"Lancet"},{"key":"473_CR66","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1001\/jama.294.1.97","volume":"294","author":"RM van Dam","year":"2005","unstructured":"van Dam, R. M. & Hu, F. B. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA 294, 97\u2013104 (2005).","journal-title":"JAMA"},{"key":"473_CR67","doi-asserted-by":"publisher","first-page":"j5024","DOI":"10.1136\/bmj.j5024","volume":"359","author":"R Poole","year":"2017","unstructured":"Poole, R. et al. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ. 359, j5024 (2017).","journal-title":"BMJ."},{"key":"473_CR68","doi-asserted-by":"publisher","first-page":"1332","DOI":"10.1038\/s41588-022-01165-1","volume":"54","author":"Z Wang","year":"2022","unstructured":"Wang, Z. et al. Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention. Nat. Genet. 54, 1332 (2022).","journal-title":"Nat. Genet."},{"key":"473_CR69","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1093\/ije\/dyx206","volume":"47","author":"MR Munafo","year":"2018","unstructured":"Munafo, M. R., Tilling, K., Taylor, A. E., Evans, D. M. & Smith, G. D. Collider scope: when selection bias can substantially influence observed associations. Int. J. Epidemiol. 47, 226\u2013235 (2018).","journal-title":"Int. J. Epidemiol."},{"key":"473_CR70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28119-9","volume":"13","author":"O Mahmoud","year":"2022","unstructured":"Mahmoud, O., Dudbridge, F., Davey Smith, G., Munafo, M. & Tilling, K. A robust method for collider bias correction in conditional genome-wide association studies. Nat. Commun. 13, 619 (2022).","journal-title":"Nat. Commun."},{"key":"473_CR71","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1111\/j.1360-0443.2009.02617.x","volume":"104","author":"J Audrain-McGovern","year":"2009","unstructured":"Audrain-McGovern, J., Rodriguez, D. & Kassel, J. D. Adolescent smoking and depression: evidence for self-medication and peer smoking mediation. Addiction 104, 1743\u20131756 (2009).","journal-title":"Addiction"},{"key":"473_CR72","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2458-9-356","volume":"9","author":"MO Chaiton","year":"2009","unstructured":"Chaiton, M. O., Cohen, J. E., O\u2019Loughlin, J. & Rehm, J. A systematic review of longitudinal studies on the association between depression and smoking in adolescents. Bmc Public Health 9, 356 (2009).","journal-title":"Bmc Public Health"},{"key":"473_CR73","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1111\/all.12095","volume":"68","author":"J Eriksson","year":"2013","unstructured":"Eriksson, J. et al. Cigarette smoking is associated with high prevalence of chronic rhinitis and low prevalence of allergic rhinitis in men. Allergy 68, 347\u2013354 (2013).","journal-title":"Allergy"},{"key":"473_CR74","doi-asserted-by":"publisher","first-page":"e1001611","DOI":"10.1371\/journal.pmed.1001611","volume":"11","author":"J Saulyte","year":"2014","unstructured":"Saulyte, J., Regueira, C., Montes-Martinez, A., Khudyakov, P. & Takkouche, B. Active or passive exposure to tobacco smoking and allergic rhinitis, allergic dermatitis, and food allergy in adults and children: a systematic review and meta-analysis. PLoS Med. 11, e1001611 (2014).","journal-title":"PLoS Med."},{"key":"473_CR75","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/ng.571","volume":"42","author":"TobaccoGenetics, C.","year":"2010","unstructured":"Tobacco & Genetics, C. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441\u2013447 (2010).","journal-title":"Nat. Genet."},{"key":"473_CR76","unstructured":"Erzurumluoglu, A. M. et al. Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. Mol. Psychiatry 25, 2392\u20132409 (2020)."},{"key":"473_CR77","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1038\/s41588-018-0121-0","volume":"50","author":"Z Zhu","year":"2018","unstructured":"Zhu, Z. et al. A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat. Genet. 50, 857\u2013864 (2018).","journal-title":"Nat. Genet."},{"key":"473_CR78","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1159\/000322915","volume":"3","author":"DR Bouchard","year":"2010","unstructured":"Bouchard, D. R., Ross, R. & Janssen, I. Coffee, Tea and Their Additives: Association with BMI and Waist Circumference. Obes. Facts 3, 345\u2013352 (2010).","journal-title":"Obes. Facts"},{"key":"473_CR79","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1007\/s00394-012-0410-9","volume":"52","author":"JA Vernarelli","year":"2013","unstructured":"Vernarelli, J. A. & Lambert, J. D. Tea consumption is inversely associated with weight status and other markers for metabolic syndrome in US adults. Eur. J. Nutr. 52, 1039\u20131048 (2013).","journal-title":"Eur. J. Nutr."},{"key":"473_CR80","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26970-w","volume":"12","author":"L Darrous","year":"2021","unstructured":"Darrous, L., Mounier, N. & Kutalik, Z. Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics. Nat. Commun. 12, 7274 (2021).","journal-title":"Nat. Commun."},{"key":"473_CR81","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1111\/joim.12737","volume":"283","author":"M Cornelis","year":"2018","unstructured":"Cornelis, M. et al. Metabolomic response to coffee consumption: application to a three\u2010stage clinical trial. J. Internal Med. 283, 544\u2013557 (2018).","journal-title":"J. Internal Med."},{"key":"473_CR82","doi-asserted-by":"publisher","first-page":"2071","DOI":"10.1093\/hmg\/ddr086","volume":"20","author":"P Sulem","year":"2011","unstructured":"Sulem, P. et al. Sequence variants at CYP1A1-CYP1A2 and AHR associate with coffee consumption. Hum. Mol. Genet. 20, 2071\u20132077 (2011).","journal-title":"Hum. Mol. Genet."},{"key":"473_CR83","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1016\/j.bcp.2008.05.025","volume":"76","author":"M Kot","year":"2008","unstructured":"Kot, M. & Daniel, W. A. The relative contribution of human cytochrome P450 isoforms to the four caffeine oxidation pathways: an in vitro comparative study with cDNA-expressed P450s including CYP2C isoforms. Biochem. Pharmacol. 76, 543\u2013551 (2008).","journal-title":"Biochem. Pharmacol."},{"key":"473_CR84","doi-asserted-by":"publisher","unstructured":"Xue, A. et al. Unravelling the complex causal effects of substance use behaviours on common diseases [GWAS summary statistics]. Zenodo https:\/\/doi.org\/10.5281\/zenodo.10596339 (2024).","DOI":"10.5281\/zenodo.10596339"},{"key":"473_CR85","doi-asserted-by":"publisher","unstructured":"Yang, J. et al. GCTA v1.93.3beta2. Zenodo https:\/\/doi.org\/10.5281\/zenodo.5226943 (2021).","DOI":"10.5281\/zenodo.5226943"},{"key":"473_CR86","doi-asserted-by":"publisher","unstructured":"Xue, A. et al. GSMR2 v1.1.1. Zenodo https:\/\/doi.org\/10.5281\/zenodo.10595875. (2024).","DOI":"10.5281\/zenodo.10595875"},{"key":"473_CR87","doi-asserted-by":"publisher","unstructured":"Zhu, Z. et al. GSMR v1.0.6. Zenodo https:\/\/doi.org\/10.5281\/zenodo.10595809 (2024).","DOI":"10.5281\/zenodo.10595809"},{"key":"473_CR88","doi-asserted-by":"publisher","unstructured":"Xue, A. et al. Unravelling the complex causal effects of substance use behaviours on common diseases [analysis code]. Zenodo https:\/\/doi.org\/10.5281\/zenodo.10586539 (2024).","DOI":"10.5281\/zenodo.10586539"}],"container-title":["Communications Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s43856-024-00473-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43856-024-00473-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s43856-024-00473-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T14:48:35Z","timestamp":1713883715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s43856-024-00473-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,12]]},"references-count":88,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["473"],"URL":"https:\/\/doi.org\/10.1038\/s43856-024-00473-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-3465061\/v1","asserted-by":"object"}]},"ISSN":["2730-664X"],"issn-type":[{"value":"2730-664X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,12]]},"assertion":[{"value":"7 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"43"}}