{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:22:27Z","timestamp":1791300147741,"version":"4.1.0"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"7","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_UU_00011\/1"],"award-info":[{"award-number":["MC_UU_00011\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Epidemiol"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lifecourse Mendelian randomization is a causal inference technique which harnesses genetic variants with time-varying effects to develop insight into the influence of age-dependent lifestyle factors on disease risk. Here, we apply this approach to evaluate whether childhood body size has a direct consequence on 8 major disease endpoints by analysing parental history data from the UK Biobank study.<\/jats:p>\n                  <jats:p>\n                    Our findings suggest that, whilst childhood body size increases later risk of outcomes such as heart disease (odds ratio (OR)\u2009=\u20091.15, 95% CI\u2009=\u20091.07 to 1.23, P\u2009=\u20097.8\u2009\u00d7\u200910\n                    <jats:sup>\u2212\u20095<\/jats:sup>\n                    ) and diabetes (OR\u2009=\u20091.43, 95% CI\u2009=\u20091.31 to 1.56, P\u2009=\u20099.4\u2009\u00d7\u200910\n                    <jats:sup>\u2212\u200915<\/jats:sup>\n                    ) based on parental history data, these findings are likely attributed to a sustained influence of being overweight for many years over the lifecourse. Likewise, we found evidence that remaining overweight throughout the lifecourse increases risk of lung cancer, which was partially mediated by lifetime smoking index. In contrast, using parental history data provided evidence that being overweight in childhood may have a protective effect on risk of breast cancer (OR\u2009=\u20090.87, 95% CI\u2009=\u20090.78 to 0.97, P\u2009=\u20090.01), corroborating findings from observational studies and large-scale genetic consortia.\n                  <\/jats:p>\n                  <jats:p>Large-scale family disease history data can provide a complementary source of evidence for epidemiological studies to exploit, particularly given that they are likely more robust to sources of selection bias (e.g. survival bias) compared to conventional case control studies. Leveraging these data using approaches such as lifecourse Mendelian randomization can help elucidate additional layers of evidence to dissect age-dependent effects on disease risk.<\/jats:p>","DOI":"10.1007\/s10654-023-01001-8","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T16:01:22Z","timestamp":1683561682000},"page":"765-769","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Leveraging family history data to disentangle time-varying effects on disease risk using lifecourse mendelian randomization"],"prefix":"10.1007","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7918-2040","authenticated-orcid":false,"given":"Tom G","family":"Richardson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Urquijo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael V","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Davey Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,8]]},"reference":[{"issue":"1","key":"1001_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","volume":"32","author":"G Davey Smith","year":"2003","unstructured":"Davey Smith G, Ebrahim S. Mendelian randomization\u2019: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1\u201322.","journal-title":"Int J Epidemiol"},{"key":"1001_CR2","doi-asserted-by":"crossref","unstructured":"Richmond RC, Davey Smith G. Mendelian Randomization: Concepts and Scope.Cold Spring Harb Perspect Med. 2022;12(1).","DOI":"10.1101\/cshperspect.a040501"},{"issue":"6","key":"1001_CR3","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1097\/EDE.0000000000001072","volume":"30","author":"RAJ Smit","year":"2019","unstructured":"Smit RAJ, Trompet S, Dekkers OM, Jukema JW, le Cessie S. Survival Bias in mendelian randomization studies: a threat to causal inference. Epidemiology. 2019;30(6):813\u20136.","journal-title":"Epidemiology"},{"issue":"5","key":"1001_CR4","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1016\/j.ajhg.2020.03.007","volume":"106","author":"C DeBoever","year":"2020","unstructured":"DeBoever C, Tanigawa Y, Aguirre M, McInnes G, Lavertu A, Rivas MA. Assessing Digital phenotyping to Enhance Genetic Studies of Human Diseases. Am J Hum Genet. 2020;106(5):611\u201322.","journal-title":"Am J Hum Genet"},{"key":"1001_CR5","doi-asserted-by":"crossref","unstructured":"Barry CJ, Carslake D, Wade KH, Sanderson E, Davey Smith G. Comparison of intergenerational instrumental variable analyses of body mass index and mortality in UK Biobank.Int J Epidemiol. 2022.","DOI":"10.1093\/ije\/dyac159"},{"issue":"1","key":"1001_CR6","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1038\/s41467-022-29932-y","volume":"13","author":"TG Richardson","year":"2022","unstructured":"Richardson TG, Crouch DJM, Power GM, Morales-Berstein F, Hazelwood E, Fang S, et al. Childhood body size directly increases type 1 diabetes risk based on a lifecourse mendelian randomization approach. Nat Commun. 2022;13(1):2337.","journal-title":"Nat Commun"},{"key":"1001_CR7","doi-asserted-by":"publisher","first-page":"m1203","DOI":"10.1136\/bmj.m1203","volume":"369","author":"TG Richardson","year":"2020","unstructured":"Richardson TG, Sanderson E, Elsworth B, Tilling K, Davey Smith G. Use of genetic variation to separate the effects of early and later life adiposity on disease risk: mendelian randomisation study. BMJ. 2020;369:m1203.","journal-title":"BMJ"},{"key":"1001_CR8","doi-asserted-by":"crossref","unstructured":"Kibinge NK, Relton CL, Gaunt TR, Richardson TG. Characterizing the Causal Pathway for Genetic Variants Associated with Neurological Phenotypes Using Human Brain-Derived Proteome Data.Am J Hum Genet. 2020.","DOI":"10.1016\/j.ajhg.2020.04.007"},{"key":"1001_CR9","doi-asserted-by":"publisher","unstructured":"Waterfield S, Richardson TG, Davey Smith G, O\u2019Keeffe LM, Bell JA. Life course effects of genetic susceptibility to higher body size on body fat and lean mass: prospective cohort study. Int J Epidemiol. 2023; https:\/\/doi.org\/10.1093\/ije\/dyad029","DOI":"10.1093\/ije\/dyad029"},{"issue":"8","key":"1001_CR10","doi-asserted-by":"publisher","first-page":"1322","DOI":"10.1093\/hmg\/ddy434","volume":"28","author":"AE Taylor","year":"2019","unstructured":"Taylor AE, Richmond RC, Palviainen T, Loukola A, Wootton RE, Kaprio J, et al. The effect of body mass index on smoking behaviour and nicotine metabolism: a mendelian randomization study. Hum Mol Genet. 2019;28(8):1322\u201330.","journal-title":"Hum Mol Genet"},{"issue":"1","key":"1001_CR11","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/s42003-022-03272-5","volume":"5","author":"M Vabistsevits","year":"2022","unstructured":"Vabistsevits M, Davey Smith G, Sanderson E, Richardson TG, Lloyd-Lewis B, Richmond RC. Deciphering how early life adiposity influences breast cancer risk using mendelian randomization. Commun Biol. 2022;5(1):337.","journal-title":"Commun Biol"},{"issue":"6","key":"1001_CR12","doi-asserted-by":"publisher","first-page":"e317","DOI":"10.1016\/S2666-7568(21)00086-6","volume":"2","author":"TG Richardson","year":"2021","unstructured":"Richardson TG, Wang Q, Sanderson E, Mahajan A, McCarthy MI, Frayling TM, et al. Effects of apolipoprotein B on lifespan and risks of major diseases including type 2 diabetes: a mendelian randomisation analysis using outcomes in first-degree relatives. Lancet Healthy Longev. 2021;2(6):e317\u2013e26.","journal-title":"Lancet Healthy Longev"},{"issue":"5","key":"1001_CR13","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41588-020-0613-6","volume":"52","author":"MLA Hujoel","year":"2020","unstructured":"Hujoel MLA, Gazal S, Loh PR, Patterson N, Price AL. Liability threshold modeling of case-control status and family history of disease increases association power. Nat Genet. 2020;52(5):541\u20137.","journal-title":"Nat Genet"},{"issue":"3","key":"1001_CR14","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","volume":"51","author":"IE Jansen","year":"2019","unstructured":"Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. 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MVH is employed by 23andMe outside of this work and holds stock in the company. All other authors declare no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Ethical approval for the UK Biobank was obtained from the Research Ethics Committee (REC; approval number: 11\/NW\/0382). All analyses were undertaken under UKB application #15825.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Informed consent was collected from all participants whose data was analysed in this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All study participants consent to having their data published in journal articles.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}]}}