Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes
Julia K. Goodrich(Broad Institute), Moriel Singer‐Berk(Broad Institute), Rachel G. Son(Broad Institute), Abigail Sveden(Broad Institute), Jordan C. 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(UCLA Health), Carlos A. Aguilar‐Salinas(Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán), Gil Atzmon(Albert Einstein College of Medicine), Francisco Barajas‐Olmos(National Institute of Genomic Medicine), 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 Institutes of Health), Erwin P. Böttinger(Icahn School of Medicine at Mount Sinai), Donald W. Bowden(Wake Forest University), Federico Centeno-Cruz(National Institute of Genomic Medicine), John C. Chambers(Nanyang Technological University), Nathalie Chami(Child Health and Development Institute), Edmund Chan(National University of Singapore), Juliana C.N. Chan(Chinese University of Hong Kong), Ching‐Yu Cheng(National University of Singapore), Yoon Shin Cho(Hallym University), Cecilia Contreras-Cubas(National Institute of Genomic Medicine), Emilio J. Córdova(National Institute of Genomic Medicine), Adolfo Correa(Jackson Memorial Hospital), Ralph A. DeFronzo(The University of Texas at San Antonio Health Science Center), Ravindranath Duggirala(The University of Texas Rio Grande Valley), Josée Dupuis(Boston University), Ma. Eugenia Garay‐Sevilla(Universidad de Guanajuato), Humberto Garcia‐Ortíz(National Institute of Genomic Medicine), Christian Gieger(Helmholtz Zentrum München), Benjamin Gläser(Hadassah Medical Center), Clicerio González‐Villalpando(Instituto Nacional de Salud Pública), Ma Elena Gonzalez, Niels Grarup(University of Copenhagen), Leif Groop(University of Helsinki), Myron D. Gross(University of Minnesota), Christopher A. Haiman(Keck Hospital of USC), Sohee Han(Korea National Institute of Health), Craig L. Hanis(The University of Texas Health Science Center at Houston), Torben Hansen(University of Copenhagen), Nancy L. Heard‐Costa(Boston University), Brian E. Henderson(Keck Hospital of USC), Juan Manuel Hernandez(Universidad de Guanajuato), Mi Yeong Hwang(Korea National Institute of Health), Sergio Islas‐Andrade(National Institute of Genomic Medicine), Marit E. Jørgensen(Steno Diabetes Centers), Hyun Min Kang(University of Michigan), Bong-Jo Kim(Korea National Institute of Health), Young Jin Kim(Korea National Institute of Health), Heikki A. Koistinen(University of Helsinki), Jaspal S. Kooner(Imperial College Healthcare NHS Trust), Johanna Kuusisto(University of Eastern Finland), Soo‐Heon Kwak(Seoul National University Hospital), Markku Laakso(University of Eastern Finland), Leslie A. Lange(University of Colorado Anschutz Medical Campus), Jong‐Young Lee(Korea National Institute of Health), Juyoung Lee(Korea National Institute of Health), Donna M. Lehman(The University of Texas at San Antonio Health Science Center), Allan Linneberg(University of Copenhagen), Jianjun Liu(Agency for Science, Technology and Research), Ruth J. F. Loos(Child Health and Development Institute), Valeriya Lyssenko(University of Bergen), Ronald C.W.(Chinese University of Hong Kong), Angélica Martínez‐Hernández(National Institute of Genomic Medicine), James B. Meigs(Broad Institute), Thomas Meitinger(German Centre for Cardiovascular Research), Elvia Mendoza‐Caamal(National Institute of Genomic Medicine), Karen L. Mohlke(University of North Carolina at Chapel Hill), Andrew D. Morris(Centre for Human Genetics), Alanna C. Morrison(The University of Texas Health Science Center at Houston), Maggie C. Y. Ng(Wake Forest University), Peter M. Nilsson(Lund University), Christopher J. O’Donnell(Boston University), Lorena Orozco(National Institute of Genomic Medicine), 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 Washington Health Research Institute), Alex P. Reiner(Fred Hutch Cancer Center), M. Revilla(National Institute of Genomic Medicine), Stephen S. Rich(University of Virginia), Jerome I. Rotter(The Lundquist Institute), Danish Saleheen(Center for Non-Communicable Diseases), Claudia Schurmann(Hasso Plattner Institute), Xueling Sim(National University of Singapore), Robert 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(Helmholtz Zentrum München), Tim M. Strom(Helmholtz Zentrum München), E Shyong Tai(National University of Singapore), Claudia H.T. Tam(Chinese University of Hong Kong), Yik Ying Teo(National University of Singapore), Farook Thameem(Kuwait University), Brian Tomlinson(Macau University of Science and Technology), Russell P. Tracy(University of Vermont), Tiinamaija Tuomi(University of Helsinki), Jaakko Tuomilehto(University of Helsinki), Teresa Tusié‐Luna(Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán), Rob M. van Dam(Harvard University), Ramachandran S. Vasan(Boston University), James G. Wilson(Jackson Memorial Hospital), Daniel R. Witte(Aarhus University), Tien Yin Wong(National University of Singapore), AMP-T2D-GENES Consortia(Broad Institute), Noël P. Burtt(Broad Institute), Noah Zaitlen(Centre for Human Genetics), Mark I. McCarthy(Centre for Human Genetics), Michael Boehnke(University of Maryland, Baltimore), Toni I. Pollin(Broad Institute), Jason Flannick(Broad Institute), Josep M. Mercader(Broad Institute), Anne O’Donnell‐Luria(Broad Institute), Samantha Baxter(Broad Institute), José C. Florez(Broad Institute), Daniel G. MacArthur(Broad Institute), Miriam S. Udler(Broad Institute)
Cited by 106Open Access
Abstract
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.
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