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

Mueller SH 1 , Lai AG 1 , Valkovskaya M 2 , Michailidou K 3 , Bolla MK 4 , Wang Q 4 Show all authors , Dennis J 4 , Lush M 4 , Abu-Ful Z 5 , Ahearn TU 6 , Andrulis IL 7 , Anton-Culver H 8 , Antonenkova NN 9 , Arndt V 10 , Aronson KJ 11 , Augustinsson A 12 , Baert T 13 , Freeman LEB 6 , Beckmann MW 14 , Behrens S 15 , Benitez J 16 , Bermisheva M 17 , Blomqvist C 18 , Bogdanova NV 9 , Bojesen SE 19 , Bonanni B 20 , Brenner H 10 , Brucker SY 21 , Buys SS 22 , Castelao JE 23 , Chan TL 24 , Chang-Claude J 15 , Chanock SJ 6 , Choi JY 25 , Chung WK 26 , NBCS Collaborators , Colonna SV 22 , CTS Consortium , Cornelissen S 27 , Couch FJ 28 , Czene K 29 , Daly MB 30 , Devilee P 31 , Dörk T 32 , Dossus L 33 , Dwek M 34 , Eccles DM 35 , Ekici AB 36 , Eliassen AH 37 , Engel C 38 , Evans DG 39 , Fasching PA 14 , Fletcher O 40 , Flyger H 41 , Gago-Dominguez M 42 , Gao YT 43 , García-Closas M 6 , García-Sáenz JA 44 , Genkinger J 45 , Gentry-Maharaj A 46 , Grassmann F 29 , Guénel P 47 , Gündert M 48 , Haeberle L 14 , Hahnen E 49 , Haiman CA 50 , Håkansson N 51 , Hall P 29 , Harkness EF 52 , Harrington PA 53 , Hartikainen JM 54 , Hartman M 55 , Hein A 14 , Ho WK 56 , Hooning MJ 57 , Hoppe R 58 , Hopper JL 59 , Houlston RS 60 , Howell A 61 , Hunter DJ 62 , Huo D 63 , ABCTB Investigators , Ito H 64 , Iwasaki M 65 , Jakubowska A 66 , Janni W 67 , John EM 68 , Jones ME 60 , Jung A 15 , Kaaks R 15 , Kang D 69 , Khusnutdinova EK 17 , Kim SW 70 , Kitahara CM 71 , Koutros S 6 , Kraft P 62 , Kristensen VN 72 , Kubelka-Sabit K 73 , Kurian AW 68 , Kwong A 24 , Lacey JV 74 , Lambrechts D 75 , Le Marchand L 76 , Li J 77 , Linet M 71 , Lo WY 58 , Long J 78 , Lophatananon A 79 , Mannermaa A 54 , Manoochehri M 80 , Margolin S 81 , Matsuo K 82 , Mavroudis D 83 , Menon U 46 , Muir K 79 , Murphy RA 84 , Nevanlinna H 85 , Newman WG 39 , Niederacher D 86 , O'Brien KM 87 , Obi N 88 , Offit K 89 , Olopade OI 63 , Olshan AF 90 , Olsson H 12 , Park SK 69 , Patel AV 91 , Patel A 90 , Perou CM 92 , Peto J 93 , Pharoah PDP 4 , Plaseska-Karanfilska D 94 , Presneau N 34 , Rack B 67 , Radice P 95 , Ramachandran D 32 , Rashid MU 80 , Rennert G 5 , Romero A 96 , Ruddy KJ 97 , Ruebner M 14 , Saloustros E 98 , Sandler DP 87 , Sawyer EJ 99 , Schmidt MK 27 , Schmutzler RK 49 , Schneider MO 14 , Scott C 100 , Shah M 53 , Sharma P 101 , Shen CY 102 , Shu XO 78 , Simard J 103 , Surowy H 48 , Tamimi RM 62 , Tapper WJ 35 , Taylor JA 87 , Teo SH 104 , Teras LR 91 , Toland AE 105 , Tollenaar RAEM 106 , Torres D 80 , Torres-Mejía G 107 , Troester MA 90 , Truong T 47 , Vachon CM 108 , Vijai J 89 , Weinberg CR 109 , Wendt C 110 , Winqvist R 111 , Wolk A 51 , Wu AH 50 , Yamaji T 65 , Yang XR 6 , Yu JC 112 , Zheng W 78 , Ziogas A 8 , Ziv E 113 , Dunning AM 53 , Easton DF 4 , Hemingway H 1 , Hamann U 80 , Kuchenbaecker KB 114

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 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
  • 5 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, 35254, Haifa, Israel
  • 6 Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA
  • 7 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
  • 8 Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, 92617, USA
  • 9 N.N. Alexandrov Research Institute of Oncology and Medical Radiology, 223040, Minsk, Belarus
  • 10 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
  • 11 Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON, K7L 3N6, Canada
  • 12 Department of Cancer Epidemiology, Clinical Sciences, Lund University, 222 42, Lund, Sweden
  • 13 Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, 3000, Louvain, Belgium
  • 14 Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
  • 15 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
  • 16 Biomedical Network On Rare Diseases (CIBERER), 28029, Madrid, Spain
  • 17 Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia
  • 18 Department of Oncology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland
  • 19 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark
  • 20 Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy
  • 21 Department of Gynecology and Obstetrics, University of Tübingen, 72076, Tübingen, Germany
  • 22 Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA
  • 23 Oncology and Genetics Unit, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain
  • 24 Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China
  • 25 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, 03080, Korea
  • 26 Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA
  • 27 Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands
  • 28 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
  • 29 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden
  • 30 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
  • 31 Department of Pathology, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
  • 32 Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany
  • 33 Nutrition and Metabolism Section, International Agency for Research On Cancer (IARC-WHO), 69372, Lyon, France
  • 34 School of Life Sciences, University of Westminster, London, W1W 6UW, UK
  • 35 Faculty of Medicine, University of Southampton, Southampton, SO17 1BJ, UK
  • 36 Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany
  • 37 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
  • 38 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany
  • 39 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
  • 40 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
  • 41 Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark
  • 42 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
  • 43 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, 20032, China
  • 44 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
  • 45 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, 10032, USA
  • 46 Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK
  • 47 Center for Research in Epidemiology and Population Health (CESP), Team Exposome and Heredity, INSERM, University Paris-Saclay, 94805, Villejuif, France
  • 48 Molecular Epidemiology Group, German Cancer Research Center (DKFZ), C08069120, Heidelberg, Germany
  • 49 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937, Cologne, Germany
  • 50 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
  • 51 Institute of Environmental Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden
  • 52 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
  • 53 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK
  • 54 Translational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland
  • 55 Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, 119077, Singapore
  • 56 Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia
  • 57 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands
  • 58 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany
  • 59 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia
  • 60 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, UK
  • 61 Division of Cancer Sciences, University of Manchester, Manchester, M13 9PL, UK
  • 62 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
  • 63 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, 60637, USA
  • 64 Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan
  • 65 Division of Epidemiology, Center for Public Health Sciences, National Cancer Center Institute for Cancer Control, Tokyo, 104-0045, Japan
  • 66 Department of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland
  • 67 Department of Gynaecology and Obstetrics, University Hospital Ulm, 89075, Ulm, Germany
  • 68 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA
  • 69 Cancer Research Institute, Seoul National University, Seoul, 03080, Korea
  • 70 Department of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea
  • 71 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, 20892, USA
  • 72 Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway
  • 73 Department of Histopathology and Cytology, Clinical Hospital Acibadem Sistina, Skopje, 1000, Republic of North Macedonia
  • 74 Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, 91010, USA
  • 75 VIB Center for Cancer Biology, 3001, Louvain, Belgium
  • 76 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA
  • 77 Human Genetics Division, Genome Institute of Singapore, Singapore, 138672, Singapore
  • 78 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
  • 79 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
  • 80 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
  • 81 Department of Oncology, 118 83, Sšdersjukhuset, Stockholm, Sweden
  • 82 Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
  • 83 Department of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece
  • 84 School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
  • 85 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland
  • 86 Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225, Düsseldorf, Germany
  • 87 Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA
  • 88 Institute for Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
  • 89 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
  • 90 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
  • 91 Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA
  • 92 Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • 93 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK
  • 94 Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", MASA, Skopje, 1000, Republic of North Macedonia
  • 95 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy
  • 96 Medical Oncology Department, Hospital Universitario Puerta de Hierro, 28222, Madrid, Spain
  • 97 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA
  • 98 Department of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece
  • 99 School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, SE1 9RT, UK
  • 100 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA
  • 101 Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA
  • 102 Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
  • 103 Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada
  • 104 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, 47500, Selangor, Malaysia
  • 105 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA
  • 106 Department of Surgery, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands
  • 107 Center for Population Health Research, National Institute of Public Health, 62100, Cuernavaca, Morelos, Mexico
  • 108 Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, 55905, USA
  • 109 Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, 27709, USA
  • 110 Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden
  • 111 Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, 90570, Oulu, Finland
  • 112 Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan
  • 113 Department of Medicine, Diller Family Comprehensive Cancer Center, Institute for Human Genetics, UCSF Helen, University of California San Francisco, San Francisco, CA, 94115, USA
  • 114 Division of Psychiatry, University College London, London, UK. [email protected]
Genome Med, 2023 Jan 26;15(1):7.
PMID: 36703164 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 

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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