The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

doi:10.1007/s10552-015-0654-9

. 2015 Nov;26(11):1603-16.

doi: 10.1007/s10552-015-0654-9. Epub 2015 Sep 19.

The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Neil M Davies^{1

2}, Tom R Gaunt^{3

4}, Sarah J Lewis^{3

4}, Jeff Holly⁵, Jenny L Donovan³, Freddie C Hamdy⁶, John P Kemp^{4

7}, Rosalind Eeles^{8

9}, Doug Easton¹⁰, Zsofia Kote-Jarai⁸, Ali Amin Al Olama¹⁰, Sara Benlloch¹⁰, Kenneth Muir¹¹, Graham G Giles^{12

13}, Fredrik Wiklund¹⁴, Henrik Gronberg¹⁴, Christopher A Haiman¹⁵, Johanna Schleutker^{16

17}, Børge G Nordestgaard¹⁸, Ruth C Travis¹⁹, David Neal^{20

21}, Nora Pashayan^{22

23}, Kay-Tee Khaw²⁴, Janet L Stanford^{25

26}, William J Blot²⁷, Stephen Thibodeau²⁸, Christiane Maier^{29

30}, Adam S Kibel^{31

32}, Cezary Cybulski³³, Lisa Cannon-Albright³⁴, Hermann Brenner^{35

36

37}, Jong Park³⁸, Radka Kaneva³⁹, Jyotsna Batra⁴⁰, Manuel R Teixeira^{41

42}, Hardev Pandha⁴³; PRACTICAL consortium; Mark Lathrop^{44

45}, George Davey Smith^{3

4}, Richard M Martin^{46

47

48}

Collaborators, Affiliations

Collaborators

PRACTICAL consortium:
Margaret Cook, Angela Morgan, Artitaya Lophatananon, Cyril Fisher, Daniel Leongamornlert, Edward J Saunders, Emma J Sawyer, Koveela Govindasami, Malgorzata Tymrakiewicz, Michelle Guy, Naomi Livni, Rosemary Wilkinson, Sara Jugurnauth-Little, Steve Hazel, Tokhir Dadaev, Melissa C Southey, Liesel M Fitzgerald, John Pedersen, John Hopper, Ami Karlsson, Carin Cavalli- Bjoerkman, Jan-Erik Johansson, Jan Adolfson, Markus Aly, Michael Broms, Paer Stattin, Brian E Henderson, Fredrick Schumacher, Anssi Auvinen, Kimmo Taari, Liisa Maeaettaenen, Paula Kujala, Teemu Murtola, Teuvo L J Tammela, Tiina Wahlfors, Andreas Roder, Peter Iversen, Peter Klarskov, Sune F Nielsen, Tim J Key, Hans Wallinder, Sven Gustafsson, Jenny L Donovan, Freddie Hamdy, Angela Cox, Anne George, Athene Lane, Gemma Marsden, Michael Davis, Paul Brown, Paul Pharoah, Lisa B Signorello, Wei Zheng, Shannon K McDonnell, Daniel J Schaid, Liang Wang, Lori Tillmans, Shaun Riska, Thomas Schnoeller, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Dominika Wokozorczyk, Jan Lubiski, Wojciech Kluzniak, Katja Butterbach, Christa Stegmaier, Bernd Holleczek, Babu Zachariah, Hui-Yi Lim, Hyun Park, James Haley, Julio Pow-Sang, Maria Rincon, Selina Radlein, Thomas Sellers, Chavdar Slavov, Aleksandrina Vlahova, Atanaska Mitkova, Darina Kachakova, Elenko Popov, Svetlana Christova, Tihomir Dikov, Vanio Mitev, Allison Eckert, Amanda Spurdle, Angus Collins, Glenn Wood, Greg Malone, Judith A Clements, Kris Kerr, Megan Turner, Pamela Saunders, Peter Heathcote, Srilakshmi Srinivasan, Leire Moya, Trina Yeadon, Joana Santos, Carmen Jerónimo, Paula Paulo, Pedro Pinto, Rui Henrique, Sofia Maia, Agnieszka Michael, Andrzej Kierzek, Huihai Wu

Affiliations

¹ School of Social and Community Medicine, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.
² MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.
³ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ School of Clinical Sciences, University of Bristol, Bristol, BS10 5NB, UK.
⁶ Nuffield Department of Surgery, University of Oxford, Oxford, UK.
⁷ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
⁸ The Institute of Cancer Research, London, SM2 5NG, UK.
⁹ The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
¹⁰ Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.
¹¹ Institute of Population Health, University of Manchester, Manchester, UK.
¹² Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, Australia.
¹³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
¹⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹⁶ Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
¹⁷ Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
¹⁸ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark.
¹⁹ Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
²⁰ Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Hills Road, Box 279, Cambridge, UK.
²¹ Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
²² Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, UK.
²³ Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK.
²⁴ Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
²⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
²⁷ International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD, 20850, USA.
²⁸ Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Urology, University Hospital Ulm, Ulm, Germany.
³⁰ Institute of Human Genetics, University Hospital Ulm, Ulm, Germany.
³¹ Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street-ASB II-3, Boston, MA, 02115, USA.
³² Washington University, St. Louis, Missouri.
³³ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁴ Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
³⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁸ Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL, USA.
³⁹ Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave St, 1431, Sofia, Bulgaria.
⁴⁰ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁴¹ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
⁴² Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
⁴³ The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
⁴⁴ Commissariat à l'Energie Atomique, Center National de Génotypage, Evry, France.
⁴⁵ McGill University-Génome Québec Innovation Centre, Montreal, Canada.
⁴⁶ School of Social and Community Medicine, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.
⁴⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.
⁴⁸ Bristol Nutrition Biomedical Research Unit, National Institute for Health Research, Bristol, UK. richard.martin@bristol.ac.uk.

PMID: 26387087
PMCID: PMC4596899
DOI: 10.1007/s10552-015-0654-9

The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Neil M Davies et al. Cancer Causes Control. 2015 Nov.

. 2015 Nov;26(11):1603-16.

doi: 10.1007/s10552-015-0654-9. Epub 2015 Sep 19.

Authors

Collaborators

PRACTICAL consortium:
Margaret Cook, Angela Morgan, Artitaya Lophatananon, Cyril Fisher, Daniel Leongamornlert, Edward J Saunders, Emma J Sawyer, Koveela Govindasami, Malgorzata Tymrakiewicz, Michelle Guy, Naomi Livni, Rosemary Wilkinson, Sara Jugurnauth-Little, Steve Hazel, Tokhir Dadaev, Melissa C Southey, Liesel M Fitzgerald, John Pedersen, John Hopper, Ami Karlsson, Carin Cavalli- Bjoerkman, Jan-Erik Johansson, Jan Adolfson, Markus Aly, Michael Broms, Paer Stattin, Brian E Henderson, Fredrick Schumacher, Anssi Auvinen, Kimmo Taari, Liisa Maeaettaenen, Paula Kujala, Teemu Murtola, Teuvo L J Tammela, Tiina Wahlfors, Andreas Roder, Peter Iversen, Peter Klarskov, Sune F Nielsen, Tim J Key, Hans Wallinder, Sven Gustafsson, Jenny L Donovan, Freddie Hamdy, Angela Cox, Anne George, Athene Lane, Gemma Marsden, Michael Davis, Paul Brown, Paul Pharoah, Lisa B Signorello, Wei Zheng, Shannon K McDonnell, Daniel J Schaid, Liang Wang, Lori Tillmans, Shaun Riska, Thomas Schnoeller, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Dominika Wokozorczyk, Jan Lubiski, Wojciech Kluzniak, Katja Butterbach, Christa Stegmaier, Bernd Holleczek, Babu Zachariah, Hui-Yi Lim, Hyun Park, James Haley, Julio Pow-Sang, Maria Rincon, Selina Radlein, Thomas Sellers, Chavdar Slavov, Aleksandrina Vlahova, Atanaska Mitkova, Darina Kachakova, Elenko Popov, Svetlana Christova, Tihomir Dikov, Vanio Mitev, Allison Eckert, Amanda Spurdle, Angus Collins, Glenn Wood, Greg Malone, Judith A Clements, Kris Kerr, Megan Turner, Pamela Saunders, Peter Heathcote, Srilakshmi Srinivasan, Leire Moya, Trina Yeadon, Joana Santos, Carmen Jerónimo, Paula Paulo, Pedro Pinto, Rui Henrique, Sofia Maia, Agnieszka Michael, Andrzej Kierzek, Huihai Wu

Affiliations

¹ School of Social and Community Medicine, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.
² MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. neil.davies@bristol.ac.uk.
³ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁴ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁵ School of Clinical Sciences, University of Bristol, Bristol, BS10 5NB, UK.
⁶ Nuffield Department of Surgery, University of Oxford, Oxford, UK.
⁷ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia.
⁸ The Institute of Cancer Research, London, SM2 5NG, UK.
⁹ The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
¹⁰ Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge, UK.
¹¹ Institute of Population Health, University of Manchester, Manchester, UK.
¹² Cancer Epidemiology Centre, The Cancer Council Victoria, 615 St Kilda Road, Melbourne, VIC, Australia.
¹³ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
¹⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
¹⁵ Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
¹⁶ Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
¹⁷ Institute of Biomedical Technology/BioMediTech, University of Tampere and FimLab Laboratories, Tampere, Finland.
¹⁸ Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark.
¹⁹ Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
²⁰ Surgical Oncology (Uro-Oncology: S4), University of Cambridge, Addenbrooke's Hospital, Hills Road, Box 279, Cambridge, UK.
²¹ Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
²² Strangeways Laboratory, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge, UK.
²³ Department of Applied Health Research, University College London, 1-19 Torrington Place, London, WC1E 7HB, UK.
²⁴ Cambridge Institute of Public Health, University of Cambridge, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
²⁵ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
²⁶ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
²⁷ International Epidemiology Institute, 1455 Research Blvd., Suite 550, Rockville, MD, 20850, USA.
²⁸ Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Urology, University Hospital Ulm, Ulm, Germany.
³⁰ Institute of Human Genetics, University Hospital Ulm, Ulm, Germany.
³¹ Brigham and Women's Hospital/Dana-Farber Cancer Institute, 45 Francis Street-ASB II-3, Boston, MA, 02115, USA.
³² Washington University, St. Louis, Missouri.
³³ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁴ Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
³⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁸ Division of Cancer Prevention and Control, H. Lee Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL, USA.
³⁹ Molecular Medicine Center and Department of Medical Chemistry and Biochemistry, Medical University Sofia, 2 Zdrave St, 1431, Sofia, Bulgaria.
⁴⁰ Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
⁴¹ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
⁴² Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
⁴³ The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
⁴⁴ Commissariat à l'Energie Atomique, Center National de Génotypage, Evry, France.
⁴⁵ McGill University-Génome Québec Innovation Centre, Montreal, Canada.
⁴⁶ School of Social and Community Medicine, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.
⁴⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. richard.martin@bristol.ac.uk.
⁴⁸ Bristol Nutrition Biomedical Research Unit, National Institute for Health Research, Bristol, UK. richard.martin@bristol.ac.uk.

PMID: 26387087
PMCID: PMC4596899
DOI: 10.1007/s10552-015-0654-9

Abstract

Background: Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality.

Methods: We conducted a case-control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man's number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies.

Results: The genetic risk scores explained 6.31 and 1.46% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95% CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95% CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03).

Conclusions: We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Keywords: Body mass index; Height; Instrumental variables analysis; Mendelian randomization; Prostate cancer; Single nucleotide polymorphisms.

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Figures

**Fig. 1**
Scatter plot of effects of SNPs on prostate cancer risk by their effects on height

**Fig. 2**
Scatter plot of effects of SNPs on prostate cancer risk by their effects on BMI

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References

1. Grönberg H. Prostate cancer epidemiology. Lancet Lond Engl. 2003;361:859–864. doi: 10.1016/S0140-6736(03)12713-4. - DOI - PubMed
1. Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer: a dose–response meta-analysis of prospective studies. Ann Oncol. 2012;23:1665–1671. doi: 10.1093/annonc/mdr603. - DOI - PubMed
1. Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res. 2011;4:486–501. doi: 10.1158/1940-6207.CAPR-10-0229. - DOI - PMC - PubMed
1. Discacciati A, et al. Body mass index in early and middle-late adulthood and risk of localised, advanced and fatal prostate cancer: a population-based prospective study. Br J Cancer. 2011;105:1061–1068. doi: 10.1038/bjc.2011.319. - DOI - PMC - PubMed
1. MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control CCC. 2006;17:989–1003. doi: 10.1007/s10552-006-0049-z. - DOI - PubMed

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[1] Grönberg H. Prostate cancer epidemiology. Lancet Lond Engl. 2003;361:859–864. doi: 10.1016/S0140-6736(03)12713-4. - DOI - PubMed

[2] Grönberg H. Prostate cancer epidemiology. Lancet Lond Engl. 2003;361:859–864. doi: 10.1016/S0140-6736(03)12713-4. - DOI - PubMed

[3] Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer: a dose–response meta-analysis of prospective studies. Ann Oncol. 2012;23:1665–1671. doi: 10.1093/annonc/mdr603. - DOI - PubMed

[4] Discacciati A, Orsini N, Wolk A. Body mass index and incidence of localized and advanced prostate cancer: a dose–response meta-analysis of prospective studies. Ann Oncol. 2012;23:1665–1671. doi: 10.1093/annonc/mdr603. - DOI - PubMed

[5] Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res. 2011;4:486–501. doi: 10.1158/1940-6207.CAPR-10-0229. - DOI - PMC - PubMed

[6] Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res. 2011;4:486–501. doi: 10.1158/1940-6207.CAPR-10-0229. - DOI - PMC - PubMed

[7] Discacciati A, et al. Body mass index in early and middle-late adulthood and risk of localised, advanced and fatal prostate cancer: a population-based prospective study. Br J Cancer. 2011;105:1061–1068. doi: 10.1038/bjc.2011.319. - DOI - PMC - PubMed

[8] Discacciati A, et al. Body mass index in early and middle-late adulthood and risk of localised, advanced and fatal prostate cancer: a population-based prospective study. Br J Cancer. 2011;105:1061–1068. doi: 10.1038/bjc.2011.319. - DOI - PMC - PubMed

[9] MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control CCC. 2006;17:989–1003. doi: 10.1007/s10552-006-0049-z. - DOI - PubMed

[10] MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control CCC. 2006;17:989–1003. doi: 10.1007/s10552-006-0049-z. - DOI - PubMed

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The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Collaborators

Affiliations

The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

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