TY - JOUR
T1 - Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction
AU - Estonian Biobank Research Team
AU - 23andMe Research Team
AU - Braun, Alice
AU - Shekhar, Sudhanshu
AU - Levey, Daniel F.
AU - Straub, Peter
AU - Kraft, Julia
AU - Panagiotaropoulou, Georgia M.
AU - Heilbron, Karl
AU - Awasthi, Swapnil
AU - Meleka Hanna, Rafael
AU - Hoffmann, Sarah
AU - Stein, Maike
AU - Lehnerer, Sophie
AU - Mergenthaler, Philipp
AU - Elnahas, Abdelrahman G.
AU - Topaloudi, Apostolia
AU - Koromina, Maria
AU - Palviainen, Teemu
AU - Asbjornsdottir, Bergrun
AU - Stefansson, Hreinn
AU - Skuladóttir, Astros Th
AU - Jónsdóttir, Ingileif
AU - Stefansson, Kari
AU - Reis, Kadri
AU - Esko, Tõnu
AU - Palotie, Aarno
AU - Leypoldt, Frank
AU - Stein, Murray B.
AU - Fontanillas, Pierre
AU - Kaprio, Jaakko
AU - Gelernter, Joel
AU - Davis, Lea K.
AU - Paschou, Peristera
AU - Tannemaat, Martijn R.
AU - Verschuuren, Jan J.G.M.
AU - Kuhlenbäumer, Gregor
AU - Gregersen, Peter K.
AU - Huijbers, Maartje G.
AU - Stascheit, Frauke
AU - Meisel, Andreas
AU - Ripke, Stephan
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
KW - 1182 Biochemistry, cell and molecular biology
U2 - 10.1038/s41467-024-53595-6
DO - 10.1038/s41467-024-53595-6
M3 - Article
C2 - 39537604
AN - SCOPUS:85209357532
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 9839
ER -