Nature Communications (Nov 2024)
Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
- Alice Braun,
- Sudhanshu Shekhar,
- Daniel F. Levey,
- Peter Straub,
- Julia Kraft,
- Georgia M. Panagiotaropoulou,
- Karl Heilbron,
- Swapnil Awasthi,
- Rafael Meleka Hanna,
- Sarah Hoffmann,
- Maike Stein,
- Sophie Lehnerer,
- Philipp Mergenthaler,
- Abdelrahman G. Elnahas,
- Apostolia Topaloudi,
- Maria Koromina,
- Teemu Palviainen,
- Bergrun Asbjornsdottir,
- Hreinn Stefansson,
- Astros Th. Skuladóttir,
- Ingileif Jónsdóttir,
- Kari Stefansson,
- Kadri Reis,
- Tõnu Esko,
- Aarno Palotie,
- Frank Leypoldt,
- Murray B. Stein,
- Pierre Fontanillas,
- Estonian Biobank Research Team,
- 23andMe Research Team,
- Jaakko Kaprio,
- Joel Gelernter,
- Lea K. Davis,
- Peristera Paschou,
- Martijn R. Tannemaat,
- Jan J.G.M. Verschuuren,
- Gregor Kuhlenbäumer,
- Peter K. Gregersen,
- Maartje G. Huijbers,
- Frauke Stascheit,
- Andreas Meisel,
- Stephan Ripke
Affiliations
- Alice Braun
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Sudhanshu Shekhar
- Department of Genetics, University of North Carolina at Chapel Hill
- Daniel F. Levey
- Department of Psychiatry, Yale School of Medicine
- Peter Straub
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center
- Julia Kraft
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Georgia M. Panagiotaropoulou
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Karl Heilbron
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Swapnil Awasthi
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Rafael Meleka Hanna
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Sarah Hoffmann
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Maike Stein
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Sophie Lehnerer
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Philipp Mergenthaler
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Abdelrahman G. Elnahas
- Institute of Genomics, University of Tartu
- Apostolia Topaloudi
- Department of Biological Sciences, Purdue University, West Lafayette
- Maria Koromina
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York
- Teemu Palviainen
- Institute for Molecular Medicine FIMM, University of Helsinki
- Bergrun Asbjornsdottir
- deCODE Genetics/Amgen, Inc.
- Hreinn Stefansson
- deCODE Genetics/Amgen, Inc.
- Astros Th. Skuladóttir
- deCODE Genetics/Amgen, Inc.
- Ingileif Jónsdóttir
- deCODE Genetics/Amgen, Inc.
- Kari Stefansson
- deCODE Genetics/Amgen, Inc.
- Kadri Reis
- Institute of Genomics, University of Tartu
- Tõnu Esko
- Institute of Genomics, University of Tartu
- Aarno Palotie
- Institute for Molecular Medicine FIMM, University of Helsinki
- Frank Leypoldt
- Department of Neurology, Kiel University, Kiel
- Murray B. Stein
- Department of Psychiatry and School of Public Health, University of California San Diego, La Jolla
- Pierre Fontanillas
- 23andMe, Inc., Sunnyvale
- Estonian Biobank Research Team
- 23andMe Research Team
- Jaakko Kaprio
- Institute for Molecular Medicine FIMM, University of Helsinki
- Joel Gelernter
- Department of Psychiatry, Yale School of Medicine
- Lea K. Davis
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center
- Peristera Paschou
- Department of Biological Sciences, Purdue University, West Lafayette
- Martijn R. Tannemaat
- Leiden University Medical Center, Department of Neurology
- Jan J.G.M. Verschuuren
- Leiden University Medical Center, Department of Neurology
- Gregor Kuhlenbäumer
- Department of Neurology, Kiel University, Kiel
- Peter K. Gregersen
- Feinstein Institute for Medical Research, Northwell Health, Manhasset
- Maartje G. Huijbers
- Leiden University Medical Center, Department of Neurology
- Frauke Stascheit
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Andreas Meisel
- Department of Neurology with Experimental Neurology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- Stephan Ripke
- Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin
- DOI
- https://doi.org/10.1038/s41467-024-53595-6
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 13
Abstract
Abstract Myasthenia gravis (MG) is a rare autoantibody-mediated disease affecting the neuromuscular junction. We performed a genome-wide association study of 5708 MG cases and 432,028 controls of European ancestry and a replication study in 3989 cases and 226,643 controls provided by 23andMe Inc. We identified 12 independent genome-wide significant hits (P < 5e−8) across 11 loci. Subgroup analyses revealed two of these were associated with early-onset (at age <50) and four with late-onset MG (at age ≥ 50). Imputation of human leukocyte antigen alleles revealed inverse effect sizes for late- and early-onset, suggesting a potential modulatory influence on the time of disease manifestation. We assessed the performance of polygenic risk scores for MG, which significantly predicted disease status in an independent target cohort, explaining 4.21% of the phenotypic variation (P = 5.12e−9). With this work, we aim to enhance our understanding of the genetic architecture of MG.
