Meta-Analysis

. 2023 Jan 26;15(1):7.

doi: 10.1186/s13073-022-01152-5.

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Stefanie H Mueller¹, Alvina G Lai¹, Maria Valkovskaya², Kyriaki Michailidou^{3

4

5}, Manjeet K Bolla⁵, Qin Wang⁵, Joe Dennis⁵, Michael Lush⁵, Zomoruda Abu-Ful⁶, Thomas U Ahearn⁷, Irene L Andrulis^{8

9}, Hoda Anton-Culver¹⁰, Natalia N Antonenkova¹¹, Volker Arndt¹², Kristan J Aronson¹³, Annelie Augustinsson¹⁴, Thais Baert¹⁵, Laura E Beane Freeman⁷, Matthias W Beckmann¹⁶, Sabine Behrens¹⁷, Javier Benitez^{18

19}, Marina Bermisheva²⁰, Carl Blomqvist^{21

22}, Natalia V Bogdanova^{11

23

24}, Stig E Bojesen^{25

26

27}, Bernardo Bonanni²⁸, Hermann Brenner^{12

29

30}, Sara Y Brucker³¹, Saundra S Buys³², Jose E Castelao³³, Tsun L Chan^{34

35}, Jenny Chang-Claude^{17

36}, Stephen J Chanock⁷, Ji-Yeob Choi^{37

38

39}, Wendy K Chung⁴⁰; NBCS Collaborators; Sarah V Colonna³²; CTS Consortium; Sten Cornelissen⁴¹, Fergus J Couch⁴², Kamila Czene⁴³, Mary B Daly⁴⁴, Peter Devilee^{45

46}, Thilo Dörk²⁴, Laure Dossus⁴⁷, Miriam Dwek⁴⁸, Diana M Eccles⁴⁹, Arif B Ekici⁵⁰, A Heather Eliassen^{51

52

53}, Christoph Engel^{54

55}, D Gareth Evans^{56

57}, Peter A Fasching^{16

58}, Olivia Fletcher⁵⁹, Henrik Flyger⁶⁰, Manuela Gago-Dominguez^{61

62}, Yu-Tang Gao⁶³, Montserrat García-Closas⁷, José A García-Sáenz⁶⁴, Jeanine Genkinger⁶⁵, Aleksandra Gentry-Maharaj⁶⁶, Felix Grassmann^{43

67}, Pascal Guénel⁶⁸, Melanie Gündert^{69

70

71}, Lothar Haeberle¹⁶, Eric Hahnen^{72

73}, Christopher A Haiman⁷⁴, Niclas Håkansson⁷⁵, Per Hall^{43

76}, Elaine F Harkness^{77

78

79}, Patricia A Harrington⁸⁰, Jaana M Hartikainen^{81

82}, Mikael Hartman^{83

84}, Alexander Hein¹⁶, Weang-Kee Ho^{85

86}, Maartje J Hooning⁸⁷, Reiner Hoppe^{88

89}, John L Hopper⁹⁰, Richard S Houlston⁹¹, Anthony Howell⁹², David J Hunter^{52

93}, Dezheng Huo⁹⁴; ABCTB Investigators; Hidemi Ito^{95

96}, Motoki Iwasaki⁹⁷, Anna Jakubowska^{98

99}, Wolfgang Janni¹⁰⁰, Esther M John^{101

102}, Michael E Jones⁹¹, Audrey Jung¹⁷, Rudolf Kaaks¹⁷, Daehee Kang^{38

103}, Elza K Khusnutdinova^{20

104}, Sung-Won Kim¹⁰⁵, Cari M Kitahara¹⁰⁶, Stella Koutros⁷, Peter Kraft^{52

107}, Vessela N Kristensen^{108

109}, Katerina Kubelka-Sabit¹¹⁰, Allison W Kurian^{101

102}, Ava Kwong^{34

111

112}, James V Lacey^{113

114}, Diether Lambrechts^{115

116}, Loic Le Marchand¹¹⁷, Jingmei Li¹¹⁸, Martha Linet¹⁰⁶, Wing-Yee Lo^{88

89}, Jirong Long¹¹⁹, Artitaya Lophatananon¹²⁰, Arto Mannermaa^{81

82

121}, Mehdi Manoochehri¹²², Sara Margolin^{76

123}, Keitaro Matsuo^{96

124}, Dimitrios Mavroudis¹²⁵, Usha Menon⁶⁶, Kenneth Muir¹²⁰, Rachel A Murphy^{126

127}, Heli Nevanlinna¹²⁸, William G Newman^{56

57}, Dieter Niederacher¹²⁹, Katie M O'Brien¹³⁰, Nadia Obi¹³¹, Kenneth Offit^{132

133}, Olufunmilayo I Olopade⁹⁴, Andrew F Olshan¹³⁴, Håkan Olsson¹⁴, Sue K Park^{38

103

135}, Alpa V Patel¹³⁶, Achal Patel¹³⁴, Charles M Perou¹³⁷, Julian Peto¹³⁸, Paul D P Pharoah^{5

80}, Dijana Plaseska-Karanfilska¹³⁹, Nadege Presneau⁴⁸, Brigitte Rack¹⁰⁰, Paolo Radice¹⁴⁰, Dhanya Ramachandran²⁴, Muhammad U Rashid^{122

141}, Gad Rennert⁶, Atocha Romero¹⁴², Kathryn J Ruddy¹⁴³, Matthias Ruebner¹⁶, Emmanouil Saloustros¹⁴⁴, Dale P Sandler¹³⁰, Elinor J Sawyer¹⁴⁵, Marjanka K Schmidt^{41

146}, Rita K Schmutzler^{72

73

147}, Michael O Schneider¹⁶, Christopher Scott¹⁴⁸, Mitul Shah⁸⁰, Priyanka Sharma¹⁴⁹, Chen-Yang Shen^{150

151}, Xiao-Ou Shu¹¹⁹, Jacques Simard¹⁵², Harald Surowy^{69

70}, Rulla M Tamimi^{52

153}, William J Tapper⁴⁹, Jack A Taylor^{130

154}, Soo Hwang Teo^{86

155}, Lauren R Teras¹³⁶, Amanda E Toland¹⁵⁶, Rob A E M Tollenaar¹⁵⁷, Diana Torres^{122

158}, Gabriela Torres-Mejía¹⁵⁹, Melissa A Troester¹³⁴, Thérèse Truong⁶⁸, Celine M Vachon¹⁶⁰, Joseph Vijai^{132

133}, Clarice R Weinberg¹⁶¹, Camilla Wendt¹²³, Robert Winqvist^{162

163}, Alicja Wolk^{75

164}, Anna H Wu⁷⁴, Taiki Yamaji⁹⁷, Xiaohong R Yang⁷, Jyh-Cherng Yu¹⁶⁵, Wei Zheng¹¹⁹, Argyrios Ziogas¹⁰, Elad Ziv¹⁶⁶, Alison M Dunning⁸⁰, Douglas F Easton^{5

80}, Harry Hemingway^{1

167

168

169}, Ute Hamann^#¹²², Karoline B Kuchenbaecker^#^{170

171}

Collaborators, Affiliations

Affiliations

¹ Institute of Health Informatics, University College London, London, UK.
² Division of Psychiatry, University College London, London, UK.
³ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 35254, Haifa, Israel.
⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA.
¹¹ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus.
¹² Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹³ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada.
¹⁴ Department of Cancer Epidemiology, Clinical Sciences, Lund University, 222 42, Lund, Sweden.
¹⁵ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000, Louvain, Belgium.
¹⁶ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹⁸ Biomedical Network On Rare Diseases (CIBERER), 28029, Madrid, Spain.
¹⁹ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
²⁰ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
²¹ Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
²² Department of Oncology, Örebro University Hospital, 70185, Örebro, Sweden.
²³ Department of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
²⁴ Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
²⁵ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
²⁶ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
²⁷ Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
²⁸ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy.
²⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
³⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
³¹ Department of Gynecology and Obstetrics, University of Tübingen, 72076, Tübingen, Germany.
³² Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
³³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain.
³⁴ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China.
³⁵ Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
³⁶ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
³⁷ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea.
³⁸ Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.
³⁹ Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, 03080, Korea.
⁴⁰ Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
⁴¹ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
⁴⁵ Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁴⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁴⁷ Nutrition and Metabolism Section, International Agency for Research On Cancer (IARC-WHO), 69372, Lyon, France.
⁴⁸ School of Life Sciences, University of Westminster, London, W1W 6UW, UK.
⁴⁹ Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK.
⁵⁰ Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
⁵¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁵² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁵³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁵⁴ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
⁵⁵ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
⁵⁶ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁵⁷ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁵⁸ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁵⁹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.
⁶⁰ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
⁶¹ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pœblica Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, 15706, Santiago de Compostela, Spain.
⁶² Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
⁶³ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, 20032, China.
⁶⁴ Medical Oncology Department, Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain.
⁶⁵ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
⁶⁶ Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK.
⁶⁷ Health and Medical University, 14471, Potsdam, Germany.
⁶⁸ Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, 94805, Villejuif, France.
⁶⁹ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), C08069120, Heidelberg, Germany.
⁷⁰ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, 69120, Heidelberg, Germany.
⁷¹ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
⁷² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
⁷³ Center for Integrated Oncology (CIO), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
⁷⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁷⁵ Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
⁷⁶ Department of Oncology, 118 83, Sšdersjukhuset, Stockholm, Sweden.
⁷⁷ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.
⁷⁸ Nightingale and Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK.
⁷⁹ NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁸⁰ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
⁸¹ Translational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland.
⁸² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210, Kuopio, Finland.
⁸³ Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, 119077, Singapore.
⁸⁴ Department of Surgery, National University Health System, Singapore, 119228, Singapore.
⁸⁵ Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
⁸⁶ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, 47500, Selangor, Malaysia.
⁸⁷ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands.
⁸⁸ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany.
⁸⁹ University of Tübingen, 72074, Tübingen, Germany.
⁹⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁹¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.
⁹² Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK.
⁹³ Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
⁹⁴ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA.
⁹⁵ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
⁹⁶ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
⁹⁷ Division of Epidemiology, Center for Public Health Sciences, National Cancer Center Institute for Cancer Control, Tokyo, 104-0045, Japan.
⁹⁸ Department of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland.
⁹⁹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, 71-252, Szczecin, Poland.
¹⁰⁰ Department of Gynaecology and Obstetrics, University Hospital Ulm, 89075, Ulm, Germany.
¹⁰¹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹⁰² Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
¹⁰³ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
¹⁰⁴ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, 450000, Russia.
¹⁰⁵ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea.
¹⁰⁶ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
¹⁰⁷ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
¹⁰⁸ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway.
¹⁰⁹ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0379, Oslo, Norway.
¹¹⁰ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of North Macedonia.
¹¹¹ Department of Surgery, The University of Hong Kong, Hong Kong, China.
¹¹² Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
¹¹³ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, 91010, USA.
¹¹⁴ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, 91010, USA.
¹¹⁵ VIB Center for Cancer Biology, 3001, Louvain, Belgium.
¹¹⁶ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, 3000, Louvain, Belgium.
¹¹⁷ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
¹¹⁸ Human Genetics Division, Genome Institute of Singapore, Singapore, 138672, Singapore.
¹¹⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
¹²⁰ Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
¹²¹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
¹²² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹²³ Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden.
¹²⁴ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
¹²⁵ Department of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece.
¹²⁶ School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
¹²⁷ Cancer Control Research, BC Cancer, Vancouver, BC, V5Z 1L3, Canada.
¹²⁸ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
¹²⁹ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany.
¹³⁰ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹³¹ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
¹³² Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹³³ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹³⁴ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁵ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, 03080, South Korea.
¹³⁶ Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA.
¹³⁷ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
¹³⁹ Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA, Skopje, 1000, Republic of North Macedonia.
¹⁴⁰ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy.
¹⁴¹ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, 54000, Pakistan.
¹⁴² Medical Oncology Department, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain.
¹⁴³ Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁴⁴ Department of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece.
¹⁴⁵ School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, SE1 9RT, UK.
¹⁴⁶ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
¹⁴⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
¹⁴⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁴⁹ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA.
¹⁵⁰ Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
¹⁵¹ School of Public Health, China Medical University, Taichung, Taiwan.
¹⁵² Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada.
¹⁵³ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA.
¹⁵⁴ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹⁵⁵ Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
¹⁵⁶ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA.
¹⁵⁷ Department of Surgery, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
¹⁵⁸ Institute of Human Genetics, Pontificia Universidad Javeriana, 110231, Bogota, Colombia.
¹⁵⁹ Center for Population Health Research, National Institute of Public Health, 62100, Cuernavaca, Morelos, Mexico.
¹⁶⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁶¹ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹⁶² Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, 90570, Oulu, Finland.
¹⁶³ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90570, Oulu, Finland.
¹⁶⁴ Department of Surgical Sciences, Uppsala University, 751 05, Uppsala, Sweden.
¹⁶⁵ Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan.
¹⁶⁶ Department of Medicine, Diller Family Comprehensive Cancer Center, Institute for Human Genetics, UCSF Helen, University of California San Francisco, San Francisco, CA, 94115, USA.
¹⁶⁷ Health Data Research UK, University College London, London, UK.
¹⁶⁸ University College London Hospitals Biomedical Research Centre (UCLH BRC), London, UK.
¹⁶⁹ The Alan Turing Institute, London, UK.
¹⁷⁰ Division of Psychiatry, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk.
¹⁷¹ UCL Genetics Institute, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk.

^# Contributed equally.

PMID: 36703164
PMCID: PMC9878779
DOI: 10.1186/s13073-022-01152-5

Meta-Analysis

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Stefanie H Mueller et al. Genome Med. 2023.

. 2023 Jan 26;15(1):7.

doi: 10.1186/s13073-022-01152-5.

Authors

Affiliations

¹ Institute of Health Informatics, University College London, London, UK.
² Division of Psychiatry, University College London, London, UK.
³ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶ Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 35254, Haifa, Israel.
⁷ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁰ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA.
¹¹ N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus.
¹² Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹³ Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada.
¹⁴ Department of Cancer Epidemiology, Clinical Sciences, Lund University, 222 42, Lund, Sweden.
¹⁵ Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000, Louvain, Belgium.
¹⁶ Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
¹⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹⁸ Biomedical Network On Rare Diseases (CIBERER), 28029, Madrid, Spain.
¹⁹ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
²⁰ Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
²¹ Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
²² Department of Oncology, Örebro University Hospital, 70185, Örebro, Sweden.
²³ Department of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
²⁴ Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
²⁵ Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
²⁶ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
²⁷ Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
²⁸ Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy.
²⁹ Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
³⁰ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
³¹ Department of Gynecology and Obstetrics, University of Tübingen, 72076, Tübingen, Germany.
³² Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
³³ Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain.
³⁴ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China.
³⁵ Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, China.
³⁶ Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
³⁷ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea.
³⁸ Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.
³⁹ Institute of Health Policy and Management, Seoul National University Medical Research Center, Seoul, 03080, Korea.
⁴⁰ Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
⁴¹ Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
⁴² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
⁴³ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
⁴⁴ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
⁴⁵ Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁴⁶ Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
⁴⁷ Nutrition and Metabolism Section, International Agency for Research On Cancer (IARC-WHO), 69372, Lyon, France.
⁴⁸ School of Life Sciences, University of Westminster, London, W1W 6UW, UK.
⁴⁹ Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK.
⁵⁰ Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
⁵¹ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
⁵² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁵³ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
⁵⁴ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany.
⁵⁵ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
⁵⁶ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁵⁷ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁵⁸ David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁵⁹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.
⁶⁰ Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
⁶¹ Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Fundación Pœblica Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, 15706, Santiago de Compostela, Spain.
⁶² Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
⁶³ Department of Epidemiology, Shanghai Cancer Institute, Shanghai, 20032, China.
⁶⁴ Medical Oncology Department, Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040, Madrid, Spain.
⁶⁵ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA.
⁶⁶ Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK.
⁶⁷ Health and Medical University, 14471, Potsdam, Germany.
⁶⁸ Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, 94805, Villejuif, France.
⁶⁹ Molecular Epidemiology Group, German Cancer Research Center (DKFZ), C08069120, Heidelberg, Germany.
⁷⁰ Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, 69120, Heidelberg, Germany.
⁷¹ Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764, Neuherberg, Germany.
⁷² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
⁷³ Center for Integrated Oncology (CIO), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
⁷⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁷⁵ Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
⁷⁶ Department of Oncology, 118 83, Sšdersjukhuset, Stockholm, Sweden.
⁷⁷ Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.
⁷⁸ Nightingale and Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK.
⁷⁹ NIHR Manchester Biomedical Research Unit, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
⁸⁰ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
⁸¹ Translational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland.
⁸² Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, 70210, Kuopio, Finland.
⁸³ Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, 119077, Singapore.
⁸⁴ Department of Surgery, National University Health System, Singapore, 119228, Singapore.
⁸⁵ Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
⁸⁶ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, 47500, Selangor, Malaysia.
⁸⁷ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands.
⁸⁸ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany.
⁸⁹ University of Tübingen, 72074, Tübingen, Germany.
⁹⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁹¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK.
⁹² Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK.
⁹³ Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
⁹⁴ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA.
⁹⁵ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
⁹⁶ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
⁹⁷ Division of Epidemiology, Center for Public Health Sciences, National Cancer Center Institute for Cancer Control, Tokyo, 104-0045, Japan.
⁹⁸ Department of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland.
⁹⁹ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, 71-252, Szczecin, Poland.
¹⁰⁰ Department of Gynaecology and Obstetrics, University Hospital Ulm, 89075, Ulm, Germany.
¹⁰¹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹⁰² Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
¹⁰³ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
¹⁰⁴ Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, 450000, Russia.
¹⁰⁵ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea.
¹⁰⁶ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA.
¹⁰⁷ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
¹⁰⁸ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway.
¹⁰⁹ Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0379, Oslo, Norway.
¹¹⁰ Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of North Macedonia.
¹¹¹ Department of Surgery, The University of Hong Kong, Hong Kong, China.
¹¹² Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, China.
¹¹³ Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, 91010, USA.
¹¹⁴ City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, 91010, USA.
¹¹⁵ VIB Center for Cancer Biology, 3001, Louvain, Belgium.
¹¹⁶ Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, 3000, Louvain, Belgium.
¹¹⁷ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
¹¹⁸ Human Genetics Division, Genome Institute of Singapore, Singapore, 138672, Singapore.
¹¹⁹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
¹²⁰ Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
¹²¹ Biobank of Eastern Finland, Kuopio University Hospital, Kuopio, Finland.
¹²² Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
¹²³ Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden.
¹²⁴ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
¹²⁵ Department of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece.
¹²⁶ School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
¹²⁷ Cancer Control Research, BC Cancer, Vancouver, BC, V5Z 1L3, Canada.
¹²⁸ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
¹²⁹ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany.
¹³⁰ Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹³¹ Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
¹³² Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹³³ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
¹³⁴ Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁵ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, 03080, South Korea.
¹³⁶ Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA.
¹³⁷ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³⁸ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
¹³⁹ Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA, Skopje, 1000, Republic of North Macedonia.
¹⁴⁰ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy.
¹⁴¹ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH & RC), Lahore, 54000, Pakistan.
¹⁴² Medical Oncology Department, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain.
¹⁴³ Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁴⁴ Department of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece.
¹⁴⁵ School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, SE1 9RT, UK.
¹⁴⁶ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
¹⁴⁷ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.
¹⁴⁸ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁴⁹ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA.
¹⁵⁰ Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
¹⁵¹ School of Public Health, China Medical University, Taichung, Taiwan.
¹⁵² Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada.
¹⁵³ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, 10065, USA.
¹⁵⁴ Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹⁵⁵ Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
¹⁵⁶ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA.
¹⁵⁷ Department of Surgery, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
¹⁵⁸ Institute of Human Genetics, Pontificia Universidad Javeriana, 110231, Bogota, Colombia.
¹⁵⁹ Center for Population Health Research, National Institute of Public Health, 62100, Cuernavaca, Morelos, Mexico.
¹⁶⁰ Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, 55905, USA.
¹⁶¹ Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA.
¹⁶² Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, 90570, Oulu, Finland.
¹⁶³ Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, 90570, Oulu, Finland.
¹⁶⁴ Department of Surgical Sciences, Uppsala University, 751 05, Uppsala, Sweden.
¹⁶⁵ Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan.
¹⁶⁶ Department of Medicine, Diller Family Comprehensive Cancer Center, Institute for Human Genetics, UCSF Helen, University of California San Francisco, San Francisco, CA, 94115, USA.
¹⁶⁷ Health Data Research UK, University College London, London, UK.
¹⁶⁸ University College London Hospitals Biomedical Research Centre (UCLH BRC), London, UK.
¹⁶⁹ The Alan Turing Institute, London, UK.
¹⁷⁰ Division of Psychiatry, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk.
¹⁷¹ UCL Genetics Institute, University College London, London, UK. k.kuchenbaecker@ucl.ac.uk.

^# Contributed equally.

PMID: 36703164
PMCID: PMC9878779
DOI: 10.1186/s13073-022-01152-5

Abstract

Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.

Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.

Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10^-6) and AC058822.1 (P = 1.47 × 10^-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.

Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10^-5), demonstrating the importance of diversifying study cohorts.

Keywords: Breast cancer susceptibility; Diverse ancestry; Gene regulation; Genome-wide association study; Rare variants.

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Conflict of interest statement

S.H.M. became an employee of Boehringer Ingelheim after completing this study. Matthias W. Beckmann conducts research funded by Amgen, Novartis, and Pfizer. P.A.F. conducts research funded by Amgen, Novartis, and Pfizer. He received Honoraria from Roche, Novartis, and Pfizer. R.A.M. is a consultant for Pharmavite. A.W.K. received research funding from Myriad Genetics for an unrelated project (funding dates 2017–2019).

Figures

**Fig. 1**
Study design. A Breast cancer patients and control individuals included in this study originate from 33 different study center countries, and comprise samples of African, Asian, European, or Latin American and Hispanic ancestry. B The mummy implemented extended SKAT-O analysis includes variants located in coding regions with an extended window and variants located in linked regulatory regions. Regulatory regions were identified based on overlap with genetic range of coding features or based on presence of gene-specific eQTLs in GTEx data in those regulatory regions

**Fig. 2**
Regional Plot the *FMNL3* Gene on Chromosome 12. Regional plots for the breast cancer association of *FMNL3* at 12q13.12. A Depiction of coding regions of all coding genes (data retrieved from Ensembl biomart hg38) within the chromosomal region with *FMNL3* highlighted in blue. B Variants included in the aggregation test, plotted according to their chromosomal position and analysis weight. Highlighted in blue are variants exclusively present in the analysis of samples of diverse ancestry. C Single-marker association results based on the same samples [10], with blue solid line denoting P-value for meta-analysis of all cohorts for gene of interest (P = 1.24 × 10⁻⁵) in this study and blue dashed line denoting unadjusted P-value for all-European meta-analysis (P = 6.11 × 10⁻⁶)

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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

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