A cross-disorder dosage sensitivity map of the human genome

Ryan L Collins; Joseph T Glessner; Eleonora Porcu; Maarja Lepamets; Rhonda Brandon; Christopher Lauricella; Lide Han; Theodore Morley; Lisa-Marie Niestroj; Jacob Ulirsch; Selin Everett; Daniel P Howrigan; Philip M Boone; Jack Fu; Konrad J Karczewski; Georgios Kellaris; Chelsea Lowther; Diane Lucente; Kiana Mohajeri; Margit Nõukas; Xander Nuttle; Kaitlin E Samocha; Mi Trinh; Farid Ullah; Urmo Võsa; Epi25 Consortium; Estonian Biobank Research Team; Matthew E Hurles; Swaroop Aradhya; Erica E Davis; Hilary Finucane; James F Gusella; Aura Janze; Nicholas Katsanis; Ludmila Matyakhina; Benjamin M Neale; David Sanders; Stephanie Warren; Jennelle C Hodge; Dennis Lal; Douglas M Ruderfer; Jeanne Meck; Reedik Mägi; Tõnu Esko; Alexandre Reymond; Zoltán Kutalik; Hakon Hakonarson; Shamil Sunyaev; Harrison Brand; Michael E Talkowski

doi:10.1016/j.cell.2022.06.036

A cross-disorder dosage sensitivity map of the human genome

Cell. 2022 Aug 4;185(16):3041-3055.e25. doi: 10.1016/j.cell.2022.06.036. Epub 2022 Aug 1.

Authors

Ryan L Collins¹, Joseph T Glessner², Eleonora Porcu³, Maarja Lepamets⁴, Rhonda Brandon⁵, Christopher Lauricella⁵, Lide Han⁶, Theodore Morley⁶, Lisa-Marie Niestroj⁷, Jacob Ulirsch⁸, Selin Everett⁹, Daniel P Howrigan¹⁰, Philip M Boone¹¹, Jack Fu¹², Konrad J Karczewski¹⁰, Georgios Kellaris¹³, Chelsea Lowther¹², Diane Lucente¹⁴, Kiana Mohajeri¹⁵, Margit Nõukas⁴, Xander Nuttle¹², Kaitlin E Samocha¹⁶, Mi Trinh¹⁷, Farid Ullah¹³, Urmo Võsa¹⁸; Epi25 Consortium; Estonian Biobank Research Team; Matthew E Hurles¹⁷, Swaroop Aradhya⁵, Erica E Davis¹³, Hilary Finucane¹⁰, James F Gusella⁹, Aura Janze⁵, Nicholas Katsanis¹³, Ludmila Matyakhina⁵, Benjamin M Neale¹⁰, David Sanders¹⁹, Stephanie Warren⁵, Jennelle C Hodge²⁰, Dennis Lal²¹, Douglas M Ruderfer²², Jeanne Meck⁵, Reedik Mägi¹⁸, Tõnu Esko¹⁸, Alexandre Reymond²³, Zoltán Kutalik²⁴, Hakon Hakonarson², Shamil Sunyaev²⁵, Harrison Brand²⁶, Michael E Talkowski²⁷

Collaborators

Andres Metspalu, Reedik Mägi, Mari Nelis, Lili Milani, Tõnu Esko

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rlcollins@g.harvard.edu.
² Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, Philadelphia, PA 19104, USA.
³ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
⁴ Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
⁵ GeneDx, Gaithersburg, MD 20877, USA.
⁶ Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
⁷ Cologne Center for Genomics, University of Cologne, 51149 Cologne, Germany.
⁸ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
¹⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
¹² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹³ Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Lurie Children's Hospital, Chicago, IL 60611, USA; Departments of Pediatrics and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁴ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁵ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
¹⁷ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
¹⁸ Estonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
¹⁹ Avenue 80, Inc., Fort Wayne, IN 46802, USA.
²⁰ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
²¹ Cologne Center for Genomics, University of Cologne, 51149 Cologne, Germany; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
²² Division of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Center for Precision Medicine, Department of Biomedical Informatics, and Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
²³ Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
²⁴ Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Center for Primary Care and Public Health, University of Lausanne, 1015 Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, 1015 Lausanne, Switzerland.
²⁵ Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Medical Sciences and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
²⁶ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: hbrand@broadinstitute.org.
²⁷ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: talkowsk@broadinstitute.org.

Abstract

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

Keywords: copy-number variation; developmental disorders; disease association; dosage sensitivity; genomics; haploinsufficiency; statistical genetics; structural variation; triplosensitivity.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

DNA Copy Number Variations* / genetics
Gene Dosage
Genome, Human*
Haploinsufficiency / genetics
Humans

Abstract

Publication types

MeSH terms

Grants and funding