IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32009-5.html
   My bibliography  Save this article

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes

Author

Listed:
  • Jennifer L. Halford

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Valerie N. Morrill

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Seung Hoan Choi

    (Broad Institute of MIT and Harvard)

  • Sean J. Jurgens

    (Broad Institute of MIT and Harvard
    Amsterdam UMC)

  • Giorgio Melloni

    (Brigham and Women’s Hospital)

  • Nicholas A. Marston

    (Brigham and Women’s Hospital)

  • Lu-Chen Weng

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Victor Nauffal

    (Broad Institute of MIT and Harvard)

  • Amelia W. Hall

    (Broad Institute of MIT and Harvard)

  • Sophia Gunn

    (Boston University School of Public Health)

  • Christina A. Austin-Tse

    (Mass General Brigham Personalized Medicine
    Harvard Medical School
    Massachusetts General Hospital)

  • James P. Pirruccello

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Shaan Khurshid

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Heidi L. Rehm

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Emelia J. Benjamin

    (NHLBI and Boston University’s Framingham Heart Study
    Boston University School of Medicine
    Boston University School of Public Health)

  • Eric Boerwinkle

    (The University of Texas Health Science Center at Houston)

  • Jennifer A. Brody

    (University of Washington)

  • Adolfo Correa

    (University of Mississippi Medical Center)

  • Brandon K. Fornwalt

    (Department of Translational Data Science and Informatics, Geisinger
    Heart Institute, Geisinger
    Department of Radiology, Geisinger)

  • Namrata Gupta

    (Broad Institute of MIT and Harvard)

  • Christopher M. Haggerty

    (Department of Translational Data Science and Informatics, Geisinger
    Heart Institute, Geisinger)

  • Stephanie Harris

    (Massachusetts General Hospital)

  • Susan R. Heckbert

    (University of Washington
    University of Washington)

  • Charles C. Hong

    (University of Maryland School of Medicine)

  • Charles Kooperberg

    (Division of Public Health Sciences, Fred Hutchinson Cancer Center)

  • Henry J. Lin

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Ruth J. F. Loos

    (Icahn School of Medicine at Mount Sinai
    Icahn School of Medicine at Mount Sinai)

  • Braxton D. Mitchell

    (University of Maryland School of Medicine
    Baltimore Veterans Administration Medical Center)

  • Alanna C. Morrison

    (The University of Texas Health Science Center at Houston)

  • Wendy Post

    (Johns Hopkins Medicine)

  • Bruce M. Psaty

    (University of Washington
    University of Washington
    University of Washington)

  • Susan Redline

    (Brigham and Women’s Hospital)

  • Kenneth M. Rice

    (University of Washington)

  • Stephen S. Rich

    (University of Virginia)

  • Jerome I. Rotter

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Peter F. Schnatz

    (The Reading Hospital of Tower Health)

  • Elsayed Z. Soliman

    (Wake Forest School of Medicine)

  • Nona Sotoodehnia

    (University of Washington
    Division of Cardiology, Department of Medicine, University of Washington)

  • Eugene K. Wong

    (Massachusetts General Hospital
    Massachusetts General Hospital)

  • Marc S. Sabatine

    (Brigham and Women’s Hospital)

  • Christian T. Ruff

    (Brigham and Women’s Hospital)

  • Kathryn L. Lunetta

    (Boston University School of Public Health)

  • Patrick T. Ellinor

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

  • Steven A. Lubitz

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital)

Abstract

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P

Suggested Citation

  • Jennifer L. Halford & Valerie N. Morrill & Seung Hoan Choi & Sean J. Jurgens & Giorgio Melloni & Nicholas A. Marston & Lu-Chen Weng & Victor Nauffal & Amelia W. Hall & Sophia Gunn & Christina A. Austi, 2022. "Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32009-5
    DOI: 10.1038/s41467-022-32009-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32009-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32009-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. James P. Pirruccello & Alexander Bick & Minxian Wang & Mark Chaffin & Samuel Friedman & Jie Yao & Xiuqing Guo & Bharath Ambale Venkatesh & Kent D. Taylor & Wendy S. Post & Stephen Rich & Joao A. C. Li, 2020. "Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Jason Flannick & Josep M. Mercader & Christian Fuchsberger & Miriam S. Udler & Anubha Mahajan & Jennifer Wessel & Tanya M. Teslovich & Lizz Caulkins & Ryan Koesterer & Francisco Barajas-Olmos & Thomas, 2019. "Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls," Nature, Nature, vol. 570(7759), pages 71-76, June.
    3. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    4. Daniel Taliun & Daniel N. Harris & Michael D. Kessler & Jedidiah Carlson & Zachary A. Szpiech & Raul Torres & Sarah A. Gagliano Taliun & André Corvelo & Stephanie M. Gogarten & Hyun Min Kang & Achille, 2021. "Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program," Nature, Nature, vol. 590(7845), pages 290-299, February.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Mathias Seviiri & Matthew H. Law & Jue-Sheng Ong & Puya Gharahkhani & Pierre Fontanillas & Catherine M. Olsen & David C. Whiteman & Stuart MacGregor, 2022. "A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Parsa Akbari & Olukayode A. Sosina & Jonas Bovijn & Karl Landheer & Jonas B. Nielsen & Minhee Kim & Senem Aykul & Tanima De & Mary E. Haas & George Hindy & Nan Lin & Ian R. Dinsmore & Jonathan Z. Luo , 2022. "Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Injeong Shim & Hiroyuki Kuwahara & NingNing Chen & Mais O. Hashem & Lama AlAbdi & Mohamed Abouelhoda & Hong-Hee Won & Pradeep Natarajan & Patrick T. Ellinor & Amit V. Khera & Xin Gao & Fowzan S. Alkur, 2023. "Clinical utility of polygenic scores for cardiometabolic disease in Arabs," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Gareth Hawkes & Robin N. Beaumont & Zilin Li & Ravi Mandla & Xihao Li & Christine M. Albert & Donna K. Arnett & Allison E. Ashley-Koch & Aneel A. Ashrani & Kathleen C. Barnes & Eric Boerwinkle & Jenni, 2024. "Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Bárbara Sousa da Mota & Simone Rubinacci & Diana Ivette Cruz Dávalos & Carlos Eduardo G. Amorim & Martin Sikora & Niels N. Johannsen & Marzena H. Szmyt & Piotr Włodarczak & Anita Szczepanek & Marcin M, 2023. "Imputation of ancient human genomes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Adityanarayanan Radhakrishnan & Sam F. Friedman & Shaan Khurshid & Kenney Ng & Puneet Batra & Steven A. Lubitz & Anthony A. Philippakis & Caroline Uhler, 2023. "Cross-modal autoencoder framework learns holistic representations of cardiovascular state," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    7. Benjamin M. Jacobs & Daniel Stow & Sam Hodgson & Julia Zöllner & Miriam Samuel & Stavroula Kanoni & Saeed Bidi & Klaudia Walter & Claudia Langenberg & Ruth Dobson & Sarah Finer & Caroline Morton & Mon, 2024. "Genetic architecture of routinely acquired blood tests in a British South Asian cohort," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. Caibo Ning & Linyun Fan & Meng Jin & Wenji Wang & Zhiqiang Hu & Yimin Cai & Liangkai Chen & Zequn Lu & Ming Zhang & Can Chen & Yanmin Li & Fuwei Zhang & Wenzhuo Wang & Yizhuo Liu & Shuoni Chen & Yuan , 2023. "Genome-wide association analysis of left ventricular imaging-derived phenotypes identifies 72 risk loci and yields genetic insights into hypertrophic cardiomyopathy," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Matteo Di Scipio & Mohammad Khan & Shihong Mao & Michael Chong & Conor Judge & Nazia Pathan & Nicolas Perrot & Walter Nelson & Ricky Lali & Shuang Di & Robert Morton & Jeremy Petch & Guillaume Paré, 2023. "A versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Jacob Joseph & Chang Liu & Qin Hui & Krishna Aragam & Zeyuan Wang & Brian Charest & Jennifer E. Huffman & Jacob M. Keaton & Todd L. Edwards & Serkalem Demissie & Luc Djousse & Juan P. Casas & J. Micha, 2022. "Genetic architecture of heart failure with preserved versus reduced ejection fraction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Vincent Michaud & Eulalie Lasseaux & David J. Green & Dave T. Gerrard & Claudio Plaisant & Tomas Fitzgerald & Ewan Birney & Benoît Arveiler & Graeme C. Black & Panagiotis I. Sergouniotis, 2022. "The contribution of common regulatory and protein-coding TYR variants to the genetic architecture of albinism," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    12. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    13. Dick Schijven & Sourena Soheili-Nezhad & Simon E. Fisher & Clyde Francks, 2024. "Exome-wide analysis implicates rare protein-altering variants in human handedness," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    14. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    15. Lili Liu & Atlas Khan & Elena Sanchez-Rodriguez & Francesca Zanoni & Yifu Li & Nicholas Steers & Olivia Balderes & Junying Zhang & Priya Krithivasan & Robert A. LeDesma & Clara Fischman & Scott J. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    16. Shahram Bahrami & Kaja Nordengen & Jaroslav Rokicki & Alexey A. Shadrin & Zillur Rahman & Olav B. Smeland & Piotr P. Jaholkowski & Nadine Parker & Pravesh Parekh & Kevin S. O’Connell & Torbjørn Elvsås, 2024. "The genetic landscape of basal ganglia and implications for common brain disorders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    17. Sylvia Hartmann & Summaira Yasmeen & Benjamin M. Jacobs & Spiros Denaxas & Munir Pirmohamed & Eric R. Gamazon & Mark J. Caulfield & Harry Hemingway & Maik Pietzner & Claudia Langenberg, 2023. "ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    18. Mit Shah & Marco H. A. Inácio & Chang Lu & Pierre-Raphaël Schiratti & Sean L. Zheng & Adam Clement & Antonio Marvao & Wenjia Bai & Andrew P. King & James S. Ware & Martin R. Wilkins & Johanna Mielke &, 2023. "Environmental and genetic predictors of human cardiovascular ageing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    19. Yash Pershad & Taralynn Mack & Hannah Poisner & Yasminka A. Jakubek & Adrienne M. Stilp & Braxton D. Mitchell & Joshua P. Lewis & Eric Boerwinkle & Ruth J. F. Loos & Nathalie Chami & Zhe Wang & Kathle, 2024. "Determinants of mosaic chromosomal alteration fitness," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    20. Zhaotong Lin & Wei Pan, 2024. "A robust cis-Mendelian randomization method with application to drug target discovery," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32009-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.