Shichao Pang1, Loic Yengo2, Peter M Visscher2, Heribert Schunkert3,4, Christopher P Nelson5,6, Felix Bourier1,7, Lingyao Zeng1, Ling Li1, Thorsten Kessler1,7, Jeanette Erdmann8,9, Reedik Mägi10, Kristi Läll10, Andres Metspalu10, Bertram Mueller-Myhsok11,12,13, Nilesh J Samani5,6. 1. Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany. 2. Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia. 3. Department of Cardiology, Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany. schunkert@dhm.mhn.de. 4. Deutsches Zentrum Ffür Herz- und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. schunkert@dhm.mhn.de. 5. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK. 6. NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK. 7. Deutsches Zentrum Ffür Herz- und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. 8. Institute for Cardiogenetics, and University Heart Center, University of Lübeck, Lübeck, Germany. 9. DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Hamburg/Kiel/Lübeck, Germany. 10. Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia. 11. Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany. 12. Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 13. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Abstract
BACKGROUND: The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized. OBJECTIVES: We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors. METHODS: We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions. RESULTS: In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p < 0.01). Irrespective of the affected gene, a single risk allele multiplied the effects of all others carried by a person, resulting in a 2.9-fold stronger effect size in the top versus the bottom decile (p < 0.01) and an exponential increase in risk (R > 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer. CONCLUSIONS: Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.
BACKGROUND: The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized. OBJECTIVES: We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors. METHODS: We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions. RESULTS: In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p < 0.01). Irrespective of the affected gene, a single risk allele multiplied the effects of all others carried by a person, resulting in a 2.9-fold stronger effect size in the top versus the bottom decile (p < 0.01) and an exponential increase in risk (R > 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer. CONCLUSIONS: Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.
Authors: Joshua Elliott; Barbara Bodinier; Tom A Bond; Marc Chadeau-Hyam; Evangelos Evangelou; Karel G M Moons; Abbas Dehghan; David C Muller; Paul Elliott; Ioanna Tzoulaki Journal: JAMA Date: 2020-02-18 Impact factor: 56.272
Authors: Fredrick R Schumacher; Ali Amin Al Olama; Sonja I Berndt; Sara Benlloch; Mahbubl Ahmed; Edward J Saunders; Tokhir Dadaev; Daniel Leongamornlert; Ezequiel Anokian; Clara Cieza-Borrella; Chee Goh; Mark N Brook; Xin Sheng; Laura Fachal; Joe Dennis; Jonathan Tyrer; Kenneth Muir; Artitaya Lophatananon; Victoria L Stevens; Susan M Gapstur; Brian D Carter; Catherine M Tangen; Phyllis J Goodman; Ian M Thompson; Jyotsna Batra; Suzanne Chambers; Leire Moya; Judith Clements; Lisa Horvath; Wayne Tilley; Gail P Risbridger; Henrik Gronberg; Markus Aly; Tobias Nordström; Paul Pharoah; Nora Pashayan; Johanna Schleutker; Teuvo L J Tammela; Csilla Sipeky; Anssi Auvinen; Demetrius Albanes; Stephanie Weinstein; Alicja Wolk; Niclas Håkansson; Catharine M L West; Alison M Dunning; Neil Burnet; Lorelei A Mucci; Edward Giovannucci; Gerald L Andriole; Olivier Cussenot; Géraldine Cancel-Tassin; Stella Koutros; Laura E Beane Freeman; Karina Dalsgaard Sorensen; Torben Falck Orntoft; Michael Borre; Lovise Maehle; Eli Marie Grindedal; David E Neal; Jenny L Donovan; Freddie C Hamdy; Richard M Martin; Ruth C Travis; Tim J Key; Robert J Hamilton; Neil E Fleshner; Antonio Finelli; Sue Ann Ingles; Mariana C Stern; Barry S Rosenstein; Sarah L Kerns; Harry Ostrer; Yong-Jie Lu; Hong-Wei Zhang; Ninghan Feng; Xueying Mao; Xin Guo; Guomin Wang; Zan Sun; Graham G Giles; Melissa C Southey; Robert J MacInnis; Liesel M FitzGerald; Adam S Kibel; Bettina F Drake; Ana Vega; Antonio Gómez-Caamaño; Robert Szulkin; Martin Eklund; Manolis Kogevinas; Javier Llorca; Gemma Castaño-Vinyals; Kathryn L Penney; Meir Stampfer; Jong Y Park; Thomas A Sellers; Hui-Yi Lin; Janet L Stanford; Cezary Cybulski; Dominika Wokolorczyk; Jan Lubinski; Elaine A Ostrander; Milan S Geybels; Børge G Nordestgaard; Sune F Nielsen; Maren Weischer; Rasmus Bisbjerg; Martin Andreas Røder; Peter Iversen; Hermann Brenner; Katarina Cuk; Bernd Holleczek; Christiane Maier; Manuel Luedeke; Thomas Schnoeller; Jeri Kim; Christopher J Logothetis; Esther M John; Manuel R Teixeira; Paula Paulo; Marta Cardoso; Susan L Neuhausen; Linda Steele; Yuan Chun Ding; Kim De Ruyck; Gert De Meerleer; Piet Ost; Azad Razack; Jasmine Lim; Soo-Hwang Teo; Daniel W Lin; Lisa F Newcomb; Davor Lessel; Marija Gamulin; Tomislav Kulis; Radka Kaneva; Nawaid Usmani; Sandeep Singhal; Chavdar Slavov; Vanio Mitev; Matthew Parliament; Frank Claessens; Steven Joniau; Thomas Van den Broeck; Samantha Larkin; Paul A Townsend; Claire Aukim-Hastie; Manuela Gago-Dominguez; Jose Esteban Castelao; Maria Elena Martinez; Monique J Roobol; Guido Jenster; Ron H N van Schaik; Florence Menegaux; Thérèse Truong; Yves Akoli Koudou; Jianfeng Xu; Kay-Tee Khaw; Lisa Cannon-Albright; Hardev Pandha; Agnieszka Michael; Stephen N Thibodeau; Shannon K McDonnell; Daniel J Schaid; Sara Lindstrom; Constance Turman; Jing Ma; David J Hunter; Elio Riboli; Afshan Siddiq; Federico Canzian; Laurence N Kolonel; Loic Le Marchand; Robert N Hoover; Mitchell J Machiela; Zuxi Cui; Peter Kraft; Christopher I Amos; David V Conti; Douglas F Easton; Fredrik Wiklund; Stephen J Chanock; Brian E Henderson; Zsofia Kote-Jarai; Christopher A Haiman; Rosalind A Eeles Journal: Nat Genet Date: 2018-06-11 Impact factor: 38.330
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