ArticleCell2022
A cross-disorder dosage sensitivity map of the human genome.
Open access · greenAbstract read
In one paragraph
Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 240 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
240citing papers in PubMed, 1 pooled it
64.3field-weighted citation impact, top 1% of its field
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Who cites it
240 citing papers in PubMed, 1 synthesis or guideline pooled it, 348 citations in OpenAlex.
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- Germline determinants of risk and molecular subtype in young-onset lung cancer.medRxiv : the preprint server for health sciences · 2026Article
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- Programmable CRISPRtune dissects the transcriptional repressive activity of MeCP2.bioRxiv : the preprint server for biology · 2026Article
- Advancing risk gene discovery across the allele frequency spectrum.HGG advances · 2026Review
180 more citing papers are in PubMed but not listed here.
Corrections and comments
- Commented on by
- Commented on byMapping dosage.2022
Authors and funding
50 authors at 12 institutions in 5 countries.
Ryan L CollinsCenter 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.
Joseph T GlessnerDepartment 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.
Eleonora PorcuCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Maarja LepametsEstonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
Rhonda BrandonGeneDx, Gaithersburg, MD 20877, USA.
Christopher LauricellaGeneDx, Gaithersburg, MD 20877, USA.
Lide HanDivision of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Theodore MorleyDivision of Genetic Medicine, Department of Medicine, and Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Lisa-Marie NiestrojCologne Center for Genomics, University of Cologne, 51149 Cologne, Germany.
Jacob UlirschProgram 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.
Selin EverettCenter 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.
Daniel P HowriganCenter 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.
Philip M BooneCenter 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.
Jack FuCenter 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.
Konrad J KarczewskiCenter 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.
Georgios KellarisAdvanced 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.
Chelsea LowtherCenter 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.
Diane LucenteCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Kiana MohajeriCenter 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.
Margit NõukasEstonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia.
Xander NuttleCenter 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.
Kaitlin E SamochaCenter 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.
Mi TrinhHuman Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
Farid UllahAdvanced 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.
Urmo VõsaEstonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
Epi25 Consortium
Estonian Biobank Research Team
Matthew E HurlesHuman Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10, UK.
Swaroop AradhyaGeneDx, Gaithersburg, MD 20877, USA.
Erica E DavisAdvanced 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.
Hilary FinucaneCenter 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.
James F GusellaCenter 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.
Aura JanzeGeneDx, Gaithersburg, MD 20877, USA.
Nicholas KatsanisAdvanced 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.
Ludmila MatyakhinaGeneDx, Gaithersburg, MD 20877, USA.
Benjamin M NealeCenter 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.
David SandersAvenue 80, Inc., Fort Wayne, IN 46802, USA.
Stephanie WarrenGeneDx, Gaithersburg, MD 20877, USA.
Jennelle C HodgeDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Dennis LalCologne 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.
Douglas M RuderferDivision 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.
Jeanne MeckGeneDx, Gaithersburg, MD 20877, USA.
Reedik MägiEstonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
Tõnu EskoEstonian Genome Centre, Institute of Genomics, University of Tartu, 51010 Tartu, Estonia.
Alexandre ReymondCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Zoltán KutalikSwiss 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.
Hakon HakonarsonDepartment 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.
Shamil SunyaevProgram 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.
Harrison BrandCenter 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.
Michael E TalkowskiCenter 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.
Broad Institute · USNorthwestern University · USUniversity of Tartu · EEChildren's Hospital of Philadelphia · USSIB Swiss Institute of Bioinformatics · CHWellcome Sanger Institute · GBCleveland Clinic · USVanderbilt University Medical Center · USFWRadiology · USIndiana University School of MedicineMassachusetts General Hospital · USUniversity of Cologne · DE
Funding
Training Program in Bioinformatics and Integrative GenomicsT32HG002295 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI Peter J Park · 2001 to 2026
$15.8MThe Massachusetts General Hospital Harvard Center for Reproductive MedicineP50HD104224 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2021 to 2025
$7.8MClinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2MAssembling the Genetic Architecture of X-linked Dystonia ParkinsonismR01NS102423 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI David Cristopher Bragg, Clotilde Lagier-Tourenne · 2017 to 2026
$5.4MScalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4MFunctional Dissection of CNVs in Neurodevelopmental TraitsR01MH106826 · NIMH · LURIE CHILDREN'S HOSPITAL OF CHICAGO · PI DAVIS, ERICA ELLEN · 2015 to 2025
$4.6MIntegration of polygenic risk and facial morphometrics to decipher the genetic susceptibility of orofacial cleftingR01DE031261 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI Harrison Brand · 2022 to 2026
$3.8MMolecular mechanisms and genetic drivers of reciprocal genomic disordersR01HD096326 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2018 to 2022
$3.5MDissecting recurrent microdeletion syndromes using dual-guide genome editingR01NS093200 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI GUSELLA, JAMES F · 2015 to 2019
$2.9MDefining the Disorders of Genome OrganizationK08NS117891 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI BOONE, PHILIP MICHAEL · 2020 to 2024
$988kScalable tools and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR56MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2018 to 2018
$870kIntegrative Genomic Applications to Understand the Etiology of Unsolved Craniofacial AnomaliesR00DE026824 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI BRAND, HARRISON · 2020 to 2022
$747kNHGRI NIH HHS T32 HG002295NICHD NIH HHS P50 HD104224NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD096326NICHD NIH HHS R03 HD099547NIDCR NIH HHS R00 DE026824NIDCR NIH HHS R01 DE031261NIMH NIH HHS R01 MH106826NIMH NIH HHS R01 MH115957NIMH NIH HHS R56 MH115957NINDS NIH HHS K08 NS117891NINDS NIH HHS L30 NS093200NINDS NIH HHS R01 NS093200NINDS NIH HHS R01 NS102423
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.
Indexed as
DNA Copy Number VariationsGenome, HumanGene DosageHaploinsufficiencyHumanscopy-number variationdevelopmental disordersdisease associationdosage sensitivitygenomicshaploinsufficiencystatistical geneticsstructural variationtriplosensitivity
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