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Jonathan M Fussey, Robin N Beaumont, Andrew R Wood, Bijay Vaidya, Joel Smith, and Jessica Tyrrell

Evidence from observational studies suggest a positive association between serum thyroid-stimulating hormone (TSH) levels and differentiated thyroid carcinoma. However, the cause–effect relationship is poorly understood and these studies are susceptible to bias and confounding. This study aimed to investigate the causal role of TSH in both benign thyroid nodules and thyroid cancer in up to 451,025 UK Biobank participants, using a genetic technique, known as Mendelian randomization (MR). Hospital Episode Statistics and Cancer Registry databases were used to identify 462 patients with differentiated thyroid carcinoma and 2031 patients with benign nodular thyroid disease. MR methods using genetic variants associated with serum TSH were used to test causal relationships between TSH and the two disease outcomes. Mendelian randomization provided evidence of a causal link between TSH and both thyroid cancer and benign nodular thyroid disease. Two-sample MR suggested that a 1 s.d. higher genetically instrumented TSH (approximately 0.8 mIU/L) resulted in 4.96-fold higher odds of benign nodular disease (95% CI 2.46–9.99) and 2.00-fold higher odds of thyroid cancer (95% CI 1.09–3.70). Our results thus support a causal role for TSH in both benign nodular thyroid disease and thyroid cancer.

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Andreas Machens, Kerstin Lorenz, Frank Weber, and Henning Dralle

.2, encoding the RET transmembrane tyrosine kinase receptor. This seminal discovery offered unprecedented insights, beyond genotype-phenotype correlations ( Eng et al . 1996 , Machens et al. 2013 a ), into the molecular epidemiology of MEN 2A ( Machens

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Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Mette Madsen, Kirstine Stochholm, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Sten Schytte, Henrik Baymler Pedersen, Christoffer Holst Hahn, Jens Bentzen, Mette Gaustadnes, Torben Falck Ørntoft, Thomas van Overeem Hansen, Finn Cilius Nielsen, Kim Brixen, Anja Lisbeth Frederiksen, and Christian Godballe

clinical thyroid cancer database: DATHYRCA . Cancer Epidemiology 38 633 – 637 . ( doi:10.1016/j.canep.2014.07.009 ) Machens A Lorenz K Sekulla C Hoppner W Frank-Raue K Raue F Dralle H 2013 Molecular epidemiology of

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Andreas Machens and Henning Dralle

molecular epidemiology of the various mutations underlying MEN2 ( Machens et al . 2013 b ). Paradigm shift from the removal of target organs to targeted surgical intervention The important insight into the natural evolution of MEN2 gained over the

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Annika Vaclavicek, Justo Lorenzo Bermejo, Rita K Schmutzler, Christian Sutter, Barbara Wappenschmidt, Alfons Meindl, Marion Kiechle, Norbert Arnold, Bernhard H F Weber, Dieter Niederacher, Barbara Burwinkel, Claus R Bartram, Kari Hemminki, and Asta Försti

darker the colour, the higher the LD: black coloured squares indicate a very strong LD. The authors are grateful to Julia Schmutzhard, Helmholtz-University Group Molecular Epidemiology, DKFZ, for performance and evaluation of the whole genome

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Anand Pathak, Douglas R Stewart, Fabio R Faucz, Paraskevi Xekouki, Sara Bass, Aurelie Vogt, Xijun Zhang, Joseph Boland, Meredith Yeager, Jennifer T Loud, Katherine L Nathanson, Katherine A McGlynn, Constantine A Stratakis, Mark H Greene, and Lisa Mirabello

Journal of Epidemiology 165 355 – 363 . ( doi:10.1093/aje/kwk019 ). Mirabello L Kratz CP Savage SA Greene MH 2012 Promoter methylation of candidate genes associated with familial testicular cancer . International Journal of Molecular

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B Cosci, A Vivaldi, C Romei, F Gemignani, S Landi, R Ciampi, A Tacito, E Molinaro, L Agate, V Bottici, V Cappagli, D Viola, P Piaggi, P Vitti, A Pinchera, and R Elisei

substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications . Human Mutation 29 1342 – 1354 . doi:10.1002/humu.20896 . * (B Cosci and A Vivaldi contributed equally to this work)

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Frederic Castinetti, Jeffrey Moley, Lois Mulligan, and Steven G Waguespack

. New England Journal of Medicine 349 1517 – 1525 . ( ) 10.1056/NEJMoa012915 Machens A Lorenz K Sekulla C Hoppner W Frank-Raue K Raue F Dralle H 2013 Molecular epidemiology of multiple endocrine neoplasia 2

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Maria Wielsøe, Christian Bjerregaard-Olesen, Peder Kern, and Eva Cecilie Bonefeld-Jørgensen

during the collection period. Furthermore, we wish to thank our colleagues at Centre for Arctic Health & Molecular Epidemiology. They particularly want to thank Mandana Ghisari and Duy Anh Dang for support in the laboratory. References Anderson

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Minlu Zhang, Peng Peng, Kai Gu, Hui Cai, Guoyou Qin, Xiao Ou Shu, and Pingping Bao

Molecular Epidemiology Laboratory as described in detail elsewhere ( Su et al . 2011 ). Charlson Comorbidity Index was calculated for each woman based on a validated comorbidity scoring system ( Grunau et al . 2006 ). Menopausal status was defined as the