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; 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; AMP-T2D-GENES Consortia

doi:10.1038/s41467-021-23556-4

Back

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.12(1), pp.3505-3505

09/06/2021

DOI: https://doi.org/10.1038/s41467-021-23556-4

PMID: 34108472

Abstract

Adult

Biological Variation, Population

Biomarkers - metabolism

Diabetes Mellitus, Type 2 - genetics

Diabetes Mellitus, Type 2 - metabolism

Dyslipidemias - genetics

Dyslipidemias - metabolism

Exome - genetics

Genetic Predisposition to Disease - genetics

Genotype

Humans

Multifactorial Inheritance

Penetrance

Risk Assessment

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Files and links (1)

url

https://doi.org/10.1038/s41467-021-23556-4View

Published (Version of record) Open

Metrics

1 Record Views

See more details

Details

Title: Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Creators - without role: Julia K Goodrich - Broad Institute
Moriel Singer-Berk - Broad Institute
Rachel Son - Broad Institute
Abigail Sveden - Broad Institute
Jordan Wood - Broad Institute
Eleina England - Broad Institute
Joanne B Cole - Broad Institute
Ben Weisburd - Broad Institute
Nick Watts - Broad Institute
Lizz Caulkins - Broad Institute
Peter Dornbos - Broad Institute
Ryan Koesterer - Broad Institute
Zachary Zappala - Broad Institute
Haichen Zhang - University of Maryland, Baltimore
Kristin A Maloney - University of Maryland, Baltimore
Andy Dahl - Department of Neurology, UCLA, Los Angeles, CA, USA
Carlos A Aguilar-Salinas - Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Gil Atzmon - Albert Einstein College of Medicine
Francisco Barajas-Olmos - Medicina
Nir Barzilai - Albert Einstein College of Medicine
John Blangero - The University of Texas Rio Grande Valley
Eric Boerwinkle - Baylor College of Medicine
Lori L Bonnycastle - National Human Genome Research Institute
Erwin Bottinger - Icahn School of Medicine at Mount Sinai
Donald W Bowden - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
Federico Centeno-Cruz - Medicina
John C Chambers - Nanyang Technological University
Nathalie Chami - Child Health and Development Institute
Edmund Chan - Duke-NUS Medical School
Juliana Chan - Chinese University of Hong Kong
Ching-Yu Cheng - Duke-NUS Medical School
Yoon Shin Cho - Hallym University
Cecilia Contreras-Cubas - Medicina
Emilio Córdova - Medicina
Adolfo Correa - 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), San Antonio, TX, USA
Ravindranath Duggirala - The University of Texas Rio Grande Valley
Josée Dupuis - Boston University
Ma Eugenia Garay-Sevilla - Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León, Guanjuato, Mexico
Humberto García-Ortiz - Medicina
Christian Gieger - German Center for Diabetes Research
Benjamin Glaser - Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Clicerio González-Villalpando - Instituto Nacional de Salud Pública
Ma Elena Gonzalez - Centro de Estudios en Diabetes, Mexico City, Mexico
Niels Grarup - University of Copenhagen
Leif Groop - University of Helsinki
Myron Gross - University of Minnesota
Christopher Haiman - Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA
Sohee Han - Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
Craig L Hanis - The University of Texas Health Science Center at Houston
Torben Hansen - University of Copenhagen
Nancy L Heard-Costa - Boston University School of Medicine
Brian E Henderson - Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA
Juan Manuel Malacara Hernandez - Department of Medical Science, División of Health Science, University of Guanjuato. Campus León. León, Guanjuato, Mexico
Mi Yeong Hwang - Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
Sergio Islas-Andrade - Medicina
Marit E Jørgensen - University of Greenland
Hyun Min Kang - University of Michigan–Ann Arbor
Bong-Jo Kim - Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
Young Jin Kim - Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
Heikki A Koistinen - Minerva Foundation
Jaspal Singh Kooner - Imperial College London
Johanna Kuusisto - University of Eastern Finland
Soo-Heon Kwak - Seoul National University Hospital
Markku Laakso - University of Eastern Finland
Leslie Lange - University of Colorado Denver
Jong-Young Lee - Swedish Institute
Juyoung Lee - Division of Genome Research, Center for Genome Science, National Institute of Health, Chungcheongbuk-do, South Korea
Donna M Lehman - Department of Medicine, University of Texas Health San Antonio (aka University of Texas Health Science Center at San Antonio), San Antonio, TX, USA
Allan Linneberg - Rigshospitalet
Jianjun Liu - Genome Institute of Singapore
Ruth J F Loos - Child Health and Development Institute
Valeriya Lyssenko - University of Bergen
Ronald C W Ma - Chinese University of Hong Kong
Angélica Martínez-Hernández - Medicina
James B Meigs - Massachusetts General Hospital
Thomas Meitinger - German Centre for Cardiovascular Research
Elvia Mendoza-Caamal - Medicina
Karen L Mohlke - Department of Genetics, University of North Carolina Chapel Hill, Chapel Hill, NC, USA
Andrew D Morris - University of Liverpool
Alanna C Morrison - The University of Texas Health Science Center at Houston
Maggie C Y Ng - Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
Peter M Nilsson - Lund University
Christopher J O'Donnell - National Heart Lung and Blood Institute
Lorena Orozco - Medicina
Colin N A Palmer - University of Dundee
Kyong Soo Park - Seoul National University
Wendy S Post - Johns Hopkins University
Oluf Pedersen - University of Copenhagen
Michael Preuss - Icahn School of Medicine at Mount Sinai
Bruce M Psaty - Kaiser Permanente
Alexander P Reiner - Hutchinson
Cristina Revilla-Monsalve - Medicina
Stephen S Rich - University of Virginia
Jerome I Rotter - Harbor–UCLA Medical Center
Danish Saleheen - Center for Non-Communicable Diseases
Claudia Schurmann - Icahn School of Medicine at Mount Sinai
Xueling Sim - National University of Singapore
Rob Sladek - McGill University and Génome Québec Innovation Centre
Kerrin S Small - King's College London
Wing Yee So - Chinese University of Hong Kong
Timothy D Spector - King's College London
Konstantin Strauch - Institute for Medical Informatics Biometry and Epidemiology, Ludwig-Maximilians University, Munich, Germany
Tim M Strom - Helmholtz Zentrum München
E Shyong Tai - Duke-NUS Medical School
Claudia H T Tam - Chinese University of Hong Kong
Yik Ying Teo - Duke-NUS Medical School
Farook Thameem - Kuwait University
Brian Tomlinson - Faculty
Russell P Tracy - University of Vermont
Tiinamaija Tuomi - University of Helsinki
Jaakko Tuomilehto - Instituto de Salud Carlos III
Teresa Tusié-Luna - Medicina
Rob M van Dam - Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
Ramachandran S Vasan - Boston University School of Medicine
James G Wilson - University of Mississippi Medical Center
Daniel R Witte - Danish Diabetes Academy
Tien-Yin Wong - Duke-NUS Medical School
Noël P Burtt - Broad Institute
Noah Zaitlen - Department of Neurology, UCLA, Los Angeles, CA, USA
Mark I McCarthy - Genentech
Michael Boehnke - University of Michigan–Ann Arbor
Toni I Pollin - University of Maryland, Baltimore
Jason Flannick - Harvard Medical School
Josep M Mercader - Harvard Medical School
Anne O'Donnell-Luria - Harvard Medical School
Samantha Baxter - Broad Institute
Jose C Florez - Harvard Medical School
Daniel G MacArthur - Murdoch Children's Research Institute
Miriam S Udler - Harvard Medical School
AMP-T2D-GENES Consortia
Publication Details: Nature communications, Vol.12(1), pp.3505-3505
Grant note: R01 DK125490 / NIDDK NIH HHS R01 DK062370 / NIDDK NIH HHS K12 HD052896 / NICHD NIH HHS R01 DK072193 / NIDDK NIH HHS R01 DK093757 / NIDDK NIH HHS UM1 DK078616 / NIDDK NIH HHS P60 DK020541 / NIDDK NIH HHS K24 DK110550 / NIDDK NIH HHS R01 HG006399 / NHGRI NIH HHS MC_QA137853 / Medical Research Council MR/M501633/1 / Medical Research Council U01 DK062370 / NIDDK NIH HHS K99 DK127196 / NIDDK NIH HHS K23 DK114551 / NIDDK NIH HHS P30 DK020541 / NIDDK NIH HHS U01 DK105554 / NIDDK NIH HHS MC_PC_17228 / Medical Research Council R56 DK062370 / NIDDK NIH HHS MC_PC_13040 / Medical Research Council
Identifiers: 9935894608331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article