a. ecac study collaborators (for case...

Supplementary Text for:

Genetic risk score Mendelian randomization shows obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer

Jodie N Painter1, Tracy A O’Mara1, Louise Marquart1, Penelope M Webb1, on behalf of the

AOCS Group1, 2, John Attia3, 4, Sarah E Medland1, Timothy HT Cheng5, Joe Dennis6,

Elizabeth G Holliday3, 4, Mark McEvoy4, Rodney J Scott3, 7-9, Shahana Ahmed10, Catherine S

Healey10, Mitul Shah10, Maggie Gorman5, Lynn Martin5, Shirley Hodgson11, Matthias W

Beckmann12, Arif B Ekici13, Peter A Fasching12, 14, Alexander Hein12, Matthias Rübner12,

Kamila Czene15, Hatef Darabi15, Per Hall15, Jingmei Li15, Thilo Dörk16, Matthias Dürst17, Peter

Hillemanns18, Ingo Runnebaum17, Frederic Amant19, Daniela Annibali19, Jeroen Depreeuw19-21,

Diether Lambrechts20, 21, Patrick Neven19, Julie M Cunningham22, Sean C Dowdy23, Ellen L

Goode24, Brooke L Fridley25, Stacey J Winham24, Tormund S Njølstad26, 27, Helga B

Salvesen26, 27, Jone Trovik26, 27, Henrica MJ Werner26, 27, Katie Ashton3, 8, 9, Geoffrey Otton28,

Tony Proietto28, Miriam Mints29, Emma Tham30, 31, on behalf of RENDOCAS30, Manjeet K

Bolla6, Kyriaki Michailidou6, Qin Wang6, Jonathan P Tyrer10, John L Hopper32, Julian Peto33,

Anthony J Swerdlow34, 35, Barbara Burwinkel36, 37, Hermann Brenner38-40, Alfons Meindl41,

Hiltrud Brauch40, 42, 43, Annika Lindblom30, Jenny Chang-Claude44, 45, Fergus J Couch22, 24,

Graham G Giles32, 46, 47, Vessela N Kristensen48-50, Angela Cox51, Paul D P Pharoah10, Ian

Tomlinson5, on behalf of the National Study of Endometrial Cancer Genetics Group

(NSECG)5, Alison M Dunning10, Douglas F Easton6, 10, Deborah J Thompson6*, Amanda B

Spurdle1*, on behalf of The Australian National Endometrial Cancer Study Group (ANECS)1

1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research

Institute, Brisbane, QLD, 4006, Australia.2 Peter MacCallum Cancer Center, The University of Melbourne, Melbourne, 3002,

Australia.3 Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, 2305,

Australia.4 Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health,

University of Newcastle, NSW, 2305, Australia.5 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.6 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care,

University of Cambridge, Cambridge, CB1 8RN, UK.

7 Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, 2305, Australia.8 Centre for Information Based Medicine, University of Newcastle, NSW, 2308, Australia.9 School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW,

2308, Australia.10 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of

Cambridge, Cambridge, CB1 8RN, UK.11 Department of Clinical Genetics, St George’s, University of London, London, SW17 0RE,

UK.12 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-

Alexander University Erlangen-Nuremberg, Erlangen, 91054, Germany.13 Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University

Erlangen-Nuremberg, Erlangen, 91054, Germany.14 University of California at Los Angeles, Department of Medicine, Division of

Hematology/Oncology, David Geffen School of Medicine, Los Angeles, CA, 90095, USA.15 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm,

SE-171 77, Sweden.16 Hannover Medical School, Gynaecology Research Unit, Hannover, 30625, Germany.17 Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena,

07743, Germany.18 Hannover Medical School, Clinics of Gynaecology and Obstetrics, Hannover, 30625,

Germany.19 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University

Hospitals, KU Leuven - University of Leuven, 3000, Belgium.20 Vesalius Research Center, VIB, Leuven, 3000, Belgium.21 Laboratory for Translational Genetics, Department of Oncology, University Hospitals

Leuven, Leuven, 3000, Belgium.22 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905,

USA.23 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo

Clinic, Rochester, MN, 55905, USA.24 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.25 Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, 66160,

USA.26 Centre for Cancerbiomarkers, Department of Clinical Science, The University of Bergen,

5020, Norway.27 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, 5021,

Norway.28 School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, 2308,

Australia.29 Department of Women’s and Children's Health, Karolinska Institutet, Karolinska

University Hospital, Stockholm, SE-171 77, Sweden.30 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, SE-171

77, Sweden.31 Clinical Genetics, Karolinska University Hospital Solna, Stockholm, SE-17176 77,

Sweden.32 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global

Health, The University of Melbourne, Vic, 3010, Australia.33 London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.34 Division of Genetics and Epidemiology, Institute of Cancer Research, London, SM2 5NG,

UK.35 Division of Breast Cancer Research, Institute of Cancer Research, London, SM2 5NG, UK.36 Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University

of Heidelberg, Heidelberg, 69120, Germany.37 Molecular Epidemiology Group, German Cancer Research Center, DKFZ, Heidelberg,

69120, Germany.38 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center

(DKFZ), Heidelberg, 69120, Germany.39 Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National

Center for Tumor Diseases (NCT), Heidelberg, 69120, Germany40 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ),

Heidelberg, 69120, Germany41 Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical

University of Munich, Munich, 80333, Germany.42 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, 70376,

Germany.43 University of Tübingen, Tübingen, 72074, Germany44 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg,

69120, Germany.

45 University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-

Eppendorf, Hamburg, 20246, Germany46 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Vic, 3004, Australia.47 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne,

Vic, 3004, Australia.48 Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital,

Oslo, 0310, Norway.49 The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine,

Faculty of Medicine, University of Oslo, Oslo, 0316, Norway .50 Department of Clinical Molecular Oncology, Division of Medicine, Akershus University

Hospital, Lørenskog, 1478, Norway.51 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield,

S10 2RX, UK.

INDEX

A. ECAC Study Collaborators (for case samples):..............................................................5

B. BCAC and OCAC Study Collaborators (for control samples):....................................6

C. Supplementary Acknowledgements.................................................................................6

D. Supplementary Figure 1....................................................................................................9

E. Supplementary Figure 2..................................................................................................11

F. Supplementary Figure 3..................................................................................................12

G. Supplementary Figure 4..................................................................................................13

H. References.........................................................................................................................14

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A. ECAC Study Collaborators (for case samples):

The ANECS Group comprises: AB Spurdle, PM Webb, J Young (QIMR Berghofer Medical Research Institute); Consumer representative: L McQuire; Clinical Collaborators: NSW: S Baron-Hay, D Bell, A Bonaventura, A Brand, S Braye, J Carter, F Chan, C Dalrymple, A Ferrier (deceased), G Gard, N Hacker, R Hogg, R Houghton, D Marsden, K McIlroy, G Otton, S Pather, A Proietto, G Robertson, J Scurry, R Sharma, G Wain, F Wong; Qld: J Armes, A Crandon, M Cummings, R Land, J Nicklin, L Perrin, A Obermair, B Ward; SA: M Davy, T Dodd, J Miller, M Oehler, S Paramasivum, J Pierides, F Whitehead; Tas: P Blomfield, D Challis; Vic: D Neesham, J Pyman, M Quinn, R Rome, M Weitzer; WA: B Brennan, I Hammond, Y Leung, A McCartney (deceased), C Stewart, J Thompson; Project Managers: S O'Brien, S Moore; Laboratory Manager: K Ferguson; Pathology Support: M Walsh; Admin Support: R Cicero, L Green, J Griffith, L Jackman, B Ranieri; Laboratory Assistants: M O'Brien, P Schultz; Research Nurses: B Alexander, C Baxter, H Croy, A Fitzgerald, E Herron, C Hill, M Jones, J Maidens, A Marshall, K Martin, J Mayhew, E Minehan, D Roffe, H Shirley, H Steane, A Stenlake, A Ward, S Webb, J White.

CHIBCHA (study of hereditary cancer in Europe and Latin America) collaborators include: Ma. Magdalena Echeverry de Polanco, Mabel Elena Bohórquez, Rodrigo Prieto, Angel Criollo, Carolina Ramírez, Ana Patricia Estrada, Jhon Jairo Suárez (Grupo de Citogenética Filogenia y Evolución de Poblaciones, Universidad del Tolima, Colombia); Augusto Rojas Martinez (Center for Research and Development in Health Sciences, Universidad Autónoma de Nuevo León, Monterrey, Mexico); Silvia Rogatto, Samuel Aguiar Jnr, Ericka Maria Monteiro Santos (Department of Urology, School of Medicine, UNESP - São Paulo State University, Botucatu, Brazil); Monica Sans, Valentina Colistro, Pedro C. Hidalgo, Patricia Mut (Department of Biological Anthropology, College of Humanities and Educational Sciences, University of the Republic, Magallanes, Montevideo, Uruguay); Angel Carracedo, Clara Ruiz Ponte, Ines Quntela Garcia (Fundacion Publica Galega de Medicina Xenomica, CIBERER, Genomic Medicine Group-University of Santiago de Compostela, Hospital Clinico, Santiago de Compostela, Galicia, Spain); Sergi Castellvi-Bel (Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, IDIBAPS, University of Barcelona, Barcelona, Catalonia, Spain); Manuel Teixeira (Department of Genetics, Portuguese Oncology Institute, Rua Dr, António Bernardino de Almeida, Porto, Portugal).

NECS collaborators include: Ute Hamann and Michael Gilbert.

The NSECG Group comprises: Ian Tomlinson (Oxford University); M Adams, A Al-Samarraie, S Anwar, R Athavale, S Awad, A Bali, A Barnes, G Cawdell, S Chan, K Chin, P Cornes, M Crawford, J Cullimore, S Ghaem-Maghami, R Gornall, J Green, M Hall, M Harvey, J Hawe, A Head, J Herod, M Hingorani, M Hocking, C Holland, T Hollingsworth,J Hollingworth, T Ind, R Irvine, C Irwin, M Katesmark, S Kehoe, G Kheng-Chew, K Lankester, A Linder, D Luesley, C B-Lynch,V McFarlane, R Naik, N Nicholas, D Nugent, S Oates, A Oladipo, A Papadopoulos, S Pearson, D Radstone, S Raju, A Rathmell, C Redman, M Rymer, P Sarhanis, G Sparrow, N Stuart, S Sundar, A Thompson, S Tinkler, S Trent, A Tristram, N Walji, R Woolas.

RENDOCAS investigators include: Annika Lindblom, Gerasimos Tzortzatos, Miriam Mints, Emma Tham, Ofra Castro, Kristina Gemzell-Danielsson.

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SEARCH collaborators include: Helen Baker, Caroline Baynes, Don Conroy, Bridget Curzon, Patricia Harrington, Sue Irvine, Craig Luccarini, Rebecca Mayes, Hannah Munday, Barbara Perkins, Daisy Pharoah, Radka Platte, Anne Stafford and Judy West.

B. BCAC and OCAC Study Collaborators (for control samples):

The Australian Ovarian Cancer Study Group comprises: R Stuart-Harris; NSW‐ F Kirsten, J Rutovitz, P Clingan, A Glasgow, A Proietto, S Braye, G Otton, J Shannon, T Bonaventura, J Stewart, S Begbie, M Friedlander, D Bell, S Baron-Hay, A Ferrier (deceased), G Gard, D Nevell, N Pavlakis, S Valmadre, B Young, C Camaris, R Crouch, L Edwards, N Hacker, D Marsden, G Robertson, P Beale, J Beith, J Carter, C Dalrymple, R Houghton, P Russell, L Anderson, M Links, J Grygiel, J Hill, A Brand, K Byth, R Jaworski, P Harnett, R Sharma, G Wain; QLD- D Purdie, D Whiteman, B Ward, D Papadimos, A Crandon, M Cummings, K Horwood. A Obermair, L Perrin, D Wyld, J Nicklin; SA- M Davy, MK Oehler, C Hall, T Dodd, T Healy, K Pittman, D Henderson, J Miller, J Pierdes, A Achan; TAS- P Blomfield, D Challis, R McIntosh, A Parker; VIC- B Brown, R Rome, D Allen, P Grant, S Hyde, R Laurie M Robbie, D Healy, T Jobling, T Manolitsas, J McNealage, P Rogers, B Susil, E Sumithran, I Simpson, I Haviv, K Phillips, D Rischin, S Fox, D Johnson, S Lade, P Waring, M Loughrey, N O’Callaghan, B Murray, L Mileshkin, P Allan; V Billson, J Pyman, D Neesham, M Quinn, A Hamilton, C Underhill, R Bell, LF Ng, R Blum, V Ganju; WA- I Hammond, A McCartney (deceased), C Stewart, Y Leung, M Buck, N Zeps (WARTN); AOCS Management Group- DDL Bowtell, AC Green, G Chenevix-Trench, A deFazio, D Gertig, PM Webb.

BSUCH collaborator: Peter Bugert.

ESTHER collaborators: Volker Arndt, Heiko Müller, Christa Stegmaier.

GENICA Network collaborators: Wing-Yee Lo, Christina Justenhoven, Ute Hamann, Thomas Brüning, Beate Pesch, Yon-Dschun Ko, Sylvia Rabstein, Anne Lotz, Christina Baisch, Hans-Peter Fischer, Volker Harth.

C. Supplementary Acknowledgements

The authors thank the many individuals who participated in this study and the numerous institutions and their staff who have supported recruitment.

ANECS thanks members of the Molecular Cancer Epidemiology and Cancer Genetic laboratories at QIMR Berfhofer Medical Research Institute for technical assistance, and the ANECS research team for assistance with the collection of risk factor information and blood samples. ANECS also gratefully acknowledges the cooperation of the following institutions: NSW: John Hunter Hospital, Liverpool Hospital, Mater Misericordiae Hospital (Sydney), Mater Misericordiae Hospital (Newcastle), Newcastle Private Hospital, North Shore Private Hospital, Royal Hospital for Women, Royal Prince Alfred Hospital, Royal North Shore Hospital, Royal Prince Alfred Hospital, St George Hospital; Westmead Hospital, Westmead Private Hospital; Qld: Brisbane Private Hospital, Greenslopes Hospital, Mater Misericordiae Hospitals, Royal Brisbane and Women's Hospital, Wesley Hospital, Queensland Cancer Registry; SA: Adelaide Pathology Partners, Burnside Hospital, Calvary Hospital, Flinders Medical Centre, Queen Elizabeth Hospital, Royal Adelaide Hospital, South Australian

8

Cancer Registry; Tas: Launceston Hospital, North West Regional Hospitals, Royal Hobart Hospital; Vic: Freemasons Hospital, Melbourne Pathology Services, Mercy Hospital for Women, Royal Women's Hospital, Victorian Cancer Registry; WA: King Edward Memorial Hospital, St John of God Hospitals Subiaco & Murdoch, Western Australian Cancer Registry.

SEARCH thanks the SEARCH research team for recruitment, and also acknowledges the assistance of the Eastern Cancer Registration and Information Centre for subject recruitment.

BECS thanks Reiner Strick, Silke Landrith and Sonja Oeser for their logistic support during the study.

CAHRES (formerly known as SASBAC) thanks Li Yuqing from the Genome Institute of Singapore for contributions to this study, and also acknowledges previous input to SASBAC resource creation by Anna Christensson, Boel Bissmarck, Kirsimari Aaltonen, Karl von Smitten, Nina Puolakka, Christer Halldén, Lim Siew Lan and Irene Chen, Lena U. Rosenberg, Mattias Hammarström, and Eija Flygare.

HJECS thanks Wen Zheng, Hermann Hertel, and Tjoung-Won Park-Simon at Hannover Medical School for their contribution to sample recruitment.

LES gratefully acknowledges Helena Soenen, Gilian Peuteman and Dominiek Smeets for their technical assistance.

MECS thanks Tom Sellers, Catherine Phelan, Andrew Berchuck, and Kimberly Kalli, Amanda von Bismarck, Luisa Freyer and Lisa Rogmann.

MoMaTEC thanks Britt Edvardsen, Ingjerd Bergo and Mari Kyllsø Halle for technical assistance and Inger Marie Aksnes and Tor Audun Hervig at the Blood bank, Haukeland University Hospital for assistance with control recruitment.

NECS thanks staff at the University of Newcastle and the Hunter Medical Research Institute.

NSECG thank Ella Barclay and Lynn Martin for their contribution, and acknowledge the invaluable help of the National Cancer Research Network with the collection of study participants.

QIMR Berghofer thanks Margie Wright, Lisa Bowdler, Sara Smith, Megan Campbell and Scott Gordon for control sample collection and data processing, Kerenaftali Klein for statistical advice and Brendan Ryan for assistance with the figures.

RENDOCAS thanks Berith Wejderot, Sigrid Sahlen, Tao Liu, Margareta Ström, Maria Karlsson, and Birgitta Byström for their contribution to the study.

BSUCH thanks the Medical Faculty, Mannheim, the Diemtmar Hopp Foundation and the German Cancer Research Center.

MCCS was made possible by the contribution of many people, including the original investigators and the diligent team who recruited the participants and who continue working on follow up. We would like to express our gratitude to the many thousands of Melbourne residents who continue to participate in the study.

9

The UKBGS thank Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding, and the Study participants, Study staff, and the doctors, nurses and other health care staff and data providers who have contributed to the Study. The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. In addition, the iCOGS study would not have been possible without the contributions of: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai , Sara Benlloch (PRACTICAL), Georgia Chenevix-Trench, Antonis Antoniou, Lesley McGuffog, Fergus Couch and Ken Offit (CIMBA), Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Cancer Genetic Epidemiology Laboratory (Cambridge), Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissière and Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility.

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D. Supplementary Figure 1: Relationship between endometrial cancer association effect size (this study) and published BMI effect size for 77 BMI-associated SNPs (1). A. Overall endometrial cancer association effect size; B. Endometrial cancer association effect size including only cases and controls with BMI data; C. Endometrial cancer association effect size including only cases and controls with BMI data conditioning on BMI.

A.

Pearson R for correlation between effect sizes=0.26, N=77, P-value=0.02

B.


C.

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E. Supplementary Figure 2. Relationship between endometrial cancer association effect size (this study) and published WHR effect size for 47 WHR-associated SNPs (2). SNPs reaching genome-wide significant association with WHR in analyses including women only are shown in pink, while SNPs reaching genome-wide significant association with WHR only in sex-combined analyses are shown in black.


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F: Supplementary Figure 3: Forest plot of effect sizes for the association between the 77 SNP BMIwGRS and BMI across three endometrial cancer datasets and endometrioid and non-endometrioid histologies.

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G. Supplementary Figure 4. Funnel plot of minor allele frequency corrected SNP associations with BMI, against the BMI-EC causal estimates. Each dot indicates one of the 77 BMI SNPs. The darker grey vertical line represents the random effects combined causal estimate (95% CI limits shown by lighter grey vertical lines).

Meta-analysis of the causal estimates* from each of the 77 BMI SNPs:Fixed effects: OR=1.98 (95% CI 1.67-2.36) P=1.1x10-14

Random effects: OR=2.13 (95% CI 1.67-2.72) P=1.8x10-9

Heterogeneity I2=41%PCochran’s Q = 1.5x10-4

*Note: OR cannot be interpreted in terms of kg/m2 because the BMI regression coefficients from the GIANT consortium were derived using an inverse normalised transformation of BMI.

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a. ecac study collaborators (for case...

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