Nature Communications (Jun 2021)
Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
- Julia K. Goodrich,
- Moriel Singer-Berk,
- Rachel Son,
- Abigail Sveden,
- Jordan Wood,
- Eleina England,
- Joanne B. Cole,
- Ben Weisburd,
- Nick Watts,
- Lizz Caulkins,
- Peter Dornbos,
- Ryan Koesterer,
- Zachary Zappala,
- Haichen Zhang,
- Kristin A. Maloney,
- Andy Dahl,
- Carlos A. Aguilar-Salinas,
- Gil Atzmon,
- Francisco Barajas-Olmos,
- Nir Barzilai,
- John Blangero,
- Eric Boerwinkle,
- Lori L. Bonnycastle,
- Erwin Bottinger,
- Donald W. Bowden,
- Federico Centeno-Cruz,
- John C. Chambers,
- Nathalie Chami,
- Edmund Chan,
- Juliana Chan,
- Ching-Yu Cheng,
- Yoon Shin Cho,
- Cecilia Contreras-Cubas,
- Emilio Córdova,
- Adolfo Correa,
- Ralph A. DeFronzo,
- Ravindranath Duggirala,
- Josée Dupuis,
- Ma Eugenia Garay-Sevilla,
- Humberto García-Ortiz,
- Christian Gieger,
- Benjamin Glaser,
- Clicerio González-Villalpando,
- Ma Elena Gonzalez,
- Niels Grarup,
- Leif Groop,
- Myron Gross,
- Christopher Haiman,
- Sohee Han,
- Craig L. Hanis,
- Torben Hansen,
- Nancy L. Heard-Costa,
- Brian E. Henderson,
- Juan Manuel Malacara Hernandez,
- Mi Yeong Hwang,
- Sergio Islas-Andrade,
- Marit E. Jørgensen,
- Hyun Min Kang,
- Bong-Jo Kim,
- Young Jin Kim,
- Heikki A. Koistinen,
- Jaspal Singh Kooner,
- Johanna Kuusisto,
- Soo-Heon Kwak,
- Markku Laakso,
- Leslie Lange,
- Jong-Young Lee,
- Juyoung Lee,
- Donna M. Lehman,
- Allan Linneberg,
- Jianjun Liu,
- Ruth J. F. Loos,
- Valeriya Lyssenko,
- Ronald C. W. Ma,
- Angélica Martínez-Hernández,
- James B. Meigs,
- Thomas Meitinger,
- Elvia Mendoza-Caamal,
- Karen L. Mohlke,
- Andrew D. Morris,
- Alanna C. Morrison,
- Maggie C. Y. Ng,
- Peter M. Nilsson,
- Christopher J. O’Donnell,
- Lorena Orozco,
- Colin N. A. Palmer,
- Kyong Soo Park,
- Wendy S. Post,
- Oluf Pedersen,
- Michael Preuss,
- Bruce M. Psaty,
- Alexander P. Reiner,
- Cristina Revilla-Monsalve,
- Stephen S. Rich,
- Jerome I. Rotter,
- Danish Saleheen,
- Claudia Schurmann,
- Xueling Sim,
- Rob Sladek,
- Kerrin S. Small,
- Wing Yee So,
- Timothy D. Spector,
- Konstantin Strauch,
- Tim M. Strom,
- E. Shyong Tai,
- Claudia H. T. Tam,
- Yik Ying Teo,
- Farook Thameem,
- Brian Tomlinson,
- Russell P. Tracy,
- Tiinamaija Tuomi,
- Jaakko Tuomilehto,
- Teresa Tusié-Luna,
- Rob M. van Dam,
- Ramachandran S. Vasan,
- James G. Wilson,
- Daniel R. Witte,
- Tien-Yin Wong,
- AMP-T2D-GENES Consortia,
- Noël P. Burtt,
- Noah Zaitlen,
- Mark I. McCarthy,
- Michael Boehnke,
- Toni I. Pollin,
- Jason Flannick,
- Josep M. Mercader,
- Anne O’Donnell-Luria,
- Samantha Baxter,
- Jose C. Florez,
- Daniel G. MacArthur,
- Miriam S. Udler
Affiliations
- Julia K. Goodrich
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Moriel Singer-Berk
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Rachel Son
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Abigail Sveden
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Jordan Wood
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Eleina England
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Joanne B. Cole
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Ben Weisburd
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Nick Watts
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Lizz Caulkins
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Peter Dornbos
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Ryan Koesterer
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Zachary Zappala
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Haichen Zhang
- School of Medicine, University of Maryland Baltimore
- Kristin A. Maloney
- School of Medicine, University of Maryland Baltimore
- Andy Dahl
- Department of Neurology, UCLA
- Carlos A. Aguilar-Salinas
- Instituto Nacional de Ciencias Medicas y Nutricion
- Gil Atzmon
- Department of Medicine, Albert Einstein College of Medicine
- Francisco Barajas-Olmos
- Instituto Nacional de Medicina Genómica
- Nir Barzilai
- Department of Medicine, Albert Einstein College of Medicine
- John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley
- Eric Boerwinkle
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
- Lori L. Bonnycastle
- Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health
- Erwin Bottinger
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Donald W. Bowden
- Center for Diabetes Research, Wake Forest School of Medicine
- Federico Centeno-Cruz
- Instituto Nacional de Medicina Genómica
- John C. Chambers
- Department of Epidemiology and Biostatistics, Imperial College London
- Nathalie Chami
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Edmund Chan
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
- Juliana Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong
- Ching-Yu Cheng
- Singapore Eye Research Institute, Singapore National Eye Centre
- Yoon Shin Cho
- Department of Biomedical Science, Hallym University
- Cecilia Contreras-Cubas
- Instituto Nacional de Medicina Genómica
- Emilio Córdova
- Instituto Nacional de Medicina Genómica
- Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center
- Ralph A. DeFronzo
- Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
- Ravindranath Duggirala
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley
- Josée Dupuis
- Department of Biostatistics, Boston University School of Public Health
- Ma Eugenia Garay-Sevilla
- Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León
- Humberto García-Ortiz
- Instituto Nacional de Medicina Genómica
- Christian Gieger
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Benjamin Glaser
- Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center
- Clicerio González-Villalpando
- Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Instituto Nacional de Salud Publica
- Ma Elena Gonzalez
- Centro de Estudios en Diabetes
- Niels Grarup
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Leif Groop
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre
- Myron Gross
- Department of Laboratory Medicine and Pathology, University of Minnesota
- Christopher Haiman
- Department of Preventive Medicine, Keck School of Medicine of USC
- Sohee Han
- Division of Genome Research, Center for Genome Science, National Institute of Health
- Craig L. Hanis
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
- Torben Hansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Nancy L. Heard-Costa
- Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study
- Brian E. Henderson
- Department of Preventive Medicine, Keck School of Medicine of USC
- Juan Manuel Malacara Hernandez
- Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León
- Mi Yeong Hwang
- Division of Genome Research, Center for Genome Science, National Institute of Health
- Sergio Islas-Andrade
- Instituto Nacional de Medicina Genómica
- Marit E. Jørgensen
- Steno Diabetes Center Copenhagen
- Hyun Min Kang
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan
- Bong-Jo Kim
- Division of Genome Research, Center for Genome Science, National Institute of Health
- Young Jin Kim
- Division of Genome Research, Center for Genome Science, National Institute of Health
- Heikki A. Koistinen
- Department of Public Health Solutions, Finnish Institute for Health and Welfare
- Jaspal Singh Kooner
- Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust
- Johanna Kuusisto
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
- Soo-Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital
- Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital
- Leslie Lange
- Department of Medicine, University of Colorado Denver, Anschutz Medical Campus
- Jong-Young Lee
- Oneomics Soonchunhyang Mirae Medical Center
- Juyoung Lee
- Division of Genome Research, Center for Genome Science, National Institute of Health
- Donna M. Lehman
- Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio)
- Allan Linneberg
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen
- Jianjun Liu
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
- Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Valeriya Lyssenko
- Centro de Estudios en Diabetes
- Ronald C. W. Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong
- Angélica Martínez-Hernández
- Instituto Nacional de Medicina Genómica
- James B. Meigs
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Thomas Meitinger
- Institute of Human Genetics, Technical University of Munich
- Elvia Mendoza-Caamal
- Instituto Nacional de Medicina Genómica
- Karen L. Mohlke
- Department of Genetics, University of North Carolina Chapel Hill
- Andrew D. Morris
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford
- Alanna C. Morrison
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston
- Maggie C. Y. Ng
- Center for Diabetes Research, Wake Forest School of Medicine
- Peter M. Nilsson
- Department of Clinical Sciences, Medicine, Lund University
- Christopher J. O’Donnell
- Department of Pediatrics, Harvard Medical School
- Lorena Orozco
- Instituto Nacional de Medicina Genómica
- Colin N. A. Palmer
- Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, University of Dundee
- Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital
- Wendy S. Post
- Division of Cardiology, Department of Medicine, Johns Hopkins University
- Oluf Pedersen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Michael Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington
- Alexander P. Reiner
- Fred Hutchinson Cancer Research Center
- Cristina Revilla-Monsalve
- Instituto Nacional de Medicina Genómica
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia School of Medicine
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation (formerly Los Angeles Biomedical Research Institute) at Harbor-UCLA Medical Center
- Danish Saleheen
- Division of Translational Medicine and Human Genetics, University of Pennsylvania
- Claudia Schurmann
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Rob Sladek
- Department of Human Genetics, McGill University
- Kerrin S. Small
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Wing Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong
- Timothy D. Spector
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health
- Tim M. Strom
- Institute of Human Genetics, Technical University of Munich
- E. Shyong Tai
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
- Claudia H. T. Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong
- Yik Ying Teo
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Farook Thameem
- Department of Biochemistry, Faculty of Medicine, Health Science Center, Kuwait University
- Brian Tomlinson
- Faculty of Medicine, Macau University of Science & Technology
- Russell P. Tracy
- Department of Pathology and Laboratory Medicine, The Robert Larner M.D. College of Medicine, University of Vermont
- Tiinamaija Tuomi
- Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre
- Jaakko Tuomilehto
- Public Health Promotion Unit, Finnish Institute for Health and Welfare
- Teresa Tusié-Luna
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
- Rob M. van Dam
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System
- Ramachandran S. Vasan
- Boston University and National Heart Lung and Blood Institute’s Framingham Heart Study
- James G. Wilson
- Department of Physiology and Biophysics, University of Mississippi Medical Center
- Daniel R. Witte
- Department of Public Health, Aarhus University
- Tien-Yin Wong
- Singapore Eye Research Institute, Singapore National Eye Centre
- AMP-T2D-GENES Consortia
- Noël P. Burtt
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Noah Zaitlen
- Department of Neurology, UCLA
- Mark I. McCarthy
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford
- Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan
- Toni I. Pollin
- School of Medicine, University of Maryland Baltimore
- Jason Flannick
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Josep M. Mercader
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Anne O’Donnell-Luria
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Samantha Baxter
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Jose C. Florez
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Daniel G. MacArthur
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- Miriam S. Udler
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
- DOI
- https://doi.org/10.1038/s41467-021-23556-4
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 15
Abstract
Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.
