Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.,Nature Communications

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Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.
Nature Communications ( IF 14.7 ) Pub Date : 2020-07-03 , DOI: 10.1038/s41467-020-16483-3
Yan Dora Zhang _{1,

2} , Amber N Hurson _{3,

4} , Haoyu Zhang _{3,

5} , Parichoy Pal Choudhury ₃ , Douglas F Easton _{6,

7} , Roger L Milne _{8,

9,

10} , Jacques Simard ₁₁ , Per Hall _{12,

13} , Kyriaki Michailidou _{7,

14} , Joe Dennis ₇ , Marjanka K Schmidt _{15,

16} , Jenny Chang-Claude _{17,

18} , Puya Gharahkhani ₁₉ , David Whiteman ₂₀ , Peter T Campbell ₂₁ , Michael Hoffmeister ₂₂ , Mark Jenkins ₉ , Ulrike Peters ₂₃ , Li Hsu ₂₃ , Stephen B Gruber ₂₄ , Graham Casey ₂₅ , Stephanie L Schmit ₂₆ , Tracy A O'Mara ₂₇ , Amanda B Spurdle ₂₇ , Deborah J Thompson ₇ , Ian Tomlinson _{28,

29} , Immaculata De Vivo _{30,

31} , Maria Teresa Landi ₃ , Matthew H Law ₁₉ , Mark M Iles ₃₂ , Florence Demenais ₃₃ , Rajiv Kumar ₃₄ , Stuart MacGregor ₁₉ , D Timothy Bishop ₃₅ , Sarah V Ward ₃₆ , Melissa L Bondy ₃₇ , Richard Houlston ₃₈ , John K Wiencke ₃₉ , Beatrice Melin ₄₀ , Jill Barnholtz-Sloan ₄₁ , Ben Kinnersley ₃₈ , Margaret R Wrensch ₃₉ , Christopher I Amos ₄₂ , Rayjean J Hung ₄₃ , Paul Brennan ₄₄ , James McKay ₄₄ , Neil E Caporaso ₃ , Sonja I Berndt ₃ , Brenda M Birmann ₃₀ , Nicola J Camp ₄₅ , Peter Kraft ₄₆ , Nathaniel Rothman ₃ , Susan L Slager ₄₇ , Andrew Berchuck ₄₈ , Paul D P Pharoah _{6,

7} , Thomas A Sellers ₂₆ , Simon A Gayther ₄₉ , Celeste L Pearce _{24,

50} , Ellen L Goode ₅₁ , Joellen M Schildkraut ₅₂ , Kirsten B Moysich ₅₃ , Laufey T Amundadottir ₅₄ , Eric J Jacobs ₂₁ , Alison P Klein ₅₅ , Gloria M Petersen ₅₁ , Harvey A Risch ₅₆ , Rachel Z Stolzenberg-Solomon ₃ , Brian M Wolpin ₅₇ , Donghui Li ₅₈ , Rosalind A Eeles ₅₉ , Christopher A Haiman ₂₄ , Zsofia Kote-Jarai ₅₉ , Fredrick R Schumacher ₆₀ , Ali Amin Al Olama _{61,

62} , Mark P Purdue ₃ , Ghislaine Scelo ₄₄ , Marlene D Dalgaard _{63,

64} , Mark H Greene ₆₅ , Tom Grotmol ₆₆ , Peter A Kanetsky ₂₆ , Katherine A McGlynn ₃ , Katherine L Nathanson ₆₇ , Clare Turnbull ₃₈ , Fredrik Wiklund ₁₂ , , , , , , , , , , , , , , , , , , , Stephen J Chanock ₃ , Nilanjan Chatterjee _{5,

55} , Montserrat Garcia-Closas ₃

Affiliation

Department of Statistics and Actuarial Science, Faculty of Science, The University of Hong Kong, Hong Kong SAR, China.
Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology, Södersjukhuset, Stockholm, Sweden.
Department of Electron Microscopy/Molecular Pathology and The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institution, Tampa, FL, USA.
Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
Université de Paris, UMRS-1124, Institut National de la Santé et de la Recherche Médicale (INSERM), 75006, Paris, France.
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia.
Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Department of Neurological Surgery, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden.
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Institute for Clinical and Translational Research, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Lunenfeld-Tanenbuaum Research Institute, Sinai Health System, Toronto, ON, Canada.
International Agency for Research on Cancer, World Health Organization, Lyon, France.
Division of Hematology and Hematological Malignancies, University of Utah School of Medicine, Salt Lake City, UT, USA.
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Department of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA.
Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Chronic Disease Epidemiology, Yale School of Medicine, New Haven, CT, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Division of Cancer Medicine, GI Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK.
Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Strangeways Research Laboratory, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Department of Growth and Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Department of Health Technology, Technical University of Denmark, Lyngby, Denmark.
Clinical Genetics Branch, Division of Cancer Genetics and Epidemiology, National Cancer Institute, Rockville, MD, USA.
Cancer Registry of Norway, Oslo, Norway.
Division of Translational Health and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

中文翻译：

基于十四种癌症的常见变异的多基因结构评估和风险预测。

全基因组关联研究（GWAS）已确定了数百个癌症易感位点，但进一步研究的影响仍不确定。在这里，我们分析了欧洲血统 14 个癌症部位的 GWAS 的汇总数据，以估计常见易感性变异（多基因性）的数量和潜在的效应大小分布。所有癌症都表现出高度的多基因性，至少涉及数千个基因座。我们预计，解释 80% GWAS 遗传性所需的样本量从 60,000 例睾丸癌病例到超过 1,000,000 例肺癌病例不等。与平均风险相比，潜在多基因风险评分 (PRS) 第 99 个风险百分位的受试者可达到的最大相对风险范围为睾丸癌 12 到卵巢癌 2.5。我们表明，PRS 具有对乳腺癌、结肠癌和前列腺癌进行风险分层的潜力，但由于遗传性适中且发病率较低，因此对其他癌症的风险分层效果较差。

更新日期：2020-07-03

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