Genome-wide meta-analysis of myasthenia gravis uncovers new loci and provides insights into polygenic prediction

被引：4

作者：

Braun, Alice ^{[1
,2
,3
,4
]}

Shekhar, Sudhanshu ^{[5
,6
]}

Levey, Daniel F. ^{[7
,8
]}

Straub, Peter ^{[9
,10
]}

Kraft, Julia ^{[1
,2
,3
,4
]}

Panagiotaropoulou, Georgia M. ^{[1
,2
,3
,4
]}

Heilbron, Karl ^{[1
,2
,3
,4
]}

Awasthi, Swapnil ^{[1
,2
,3
,4
]}

Meleka Hanna, Rafael ^{[2
,3
,11
,12
]}

Hoffmann, Sarah ^{[2
,3
,11
,12
]}

Stein, Maike ^{[2
,3
,11
,12
]}

Lehnerer, Sophie ^{[2
,3
,11
,12
]}

Mergenthaler, Philipp ^{[2
,3
,11
,12
,13
]}

Elnahas, Abdelrahman G. ^{[14
]}

Topaloudi, Apostolia ^{[6
]}

Koromina, Maria ^{[15
,16
,17
]}

Palviainen, Teemu ^{[18
]}

Asbjornsdottir, Bergrun ^{[19
]}

Stefansson, Hreinn ^{[19
]}

Skuladottir, Astros Th. ^{[19
]}

Jonsdottir, Ingileif ^{[19
]}

Stefansson, Kari ^{[19
]}

Reis, Kadri ^{[14
]}

Esko, Tonu ^{[14
]}

Palotie, Aarno ^{[18
]}

Leypoldt, Frank ^{[20
]}

Stein, Murray B. ^{[21
,22
]}

Fontanillas, Pierre ^{[23
]}

Kaprio, Jaakko ^{[18
]}

Gelernter, Joel ^{[7
,8
]}

Davis, Lea K. ^{[9
,10
,17
]}

Paschou, Peristera ^{[6
]}

Tannemaat, Martijn R. ^{[24
]}

Verschuuren, Jan J. G. M. ^{[24
]}

Kuhlenbaeumer, Gregor ^{[20
]}

Gregersen, Peter K. ^{[25
]}

Huijbers, Maartje G. ^{[26
]}

Stascheit, Frauke ^{[11
,12
]}

Meisel, Andreas ^{[11
,12
]}

Ripke, Stephan ^{[1
,2
,3
,4
,27
]}

机构：

[1] Charite Univ Med Berlin, Dept Psychiat & Psychotherapy, Berlin, Germany

[2] Free Univ Berlin, Berlin, Germany

[3] Humboldt Univ, Berlin, Germany

[4] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[5] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC 27599 USA

[6] Purdue Univ, Dept Biol Sci, W Lafayette, IN USA

[7] Yale Sch Med, Dept Psychiat, West Haven, CT USA

[8] Vet Affairs Connecticut Healthcare Ctr, West Haven, CT USA

[9] Vanderbilt Univ, Med Ctr, Vanderbilt Genet Inst, Nashville, TN USA

[10] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, Nashville, TN USA

[11] Charite Univ Med Berlin, Dept Neurol Expt Neurol, Hindenburgdamm 30, D-12203 Berlin, Germany

[12] Charite Univ med Berlin, Neurosci Clin Res Ctr, Berlin, Germany

[13] Univ Oxford, Radcliffe Dept Med, Oxford, England

[14] Univ Tartu, Inst Genom, Tartu, Estonia

[15] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA

[16] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA

[17] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[18] Univ Helsinki, Inst Mol Med FIMM, Helsinki, Finland

[19] deCODE Genet Amgen Inc, Reykjavik, Iceland

[20] Univ Kiel, Dept Neurol, Kiel, Schleswig Holst, Germany

[21] Univ Calif San Diego, Sch Publ Hlth, Dept Psychiat, La Jolla, CA USA

[22] Psychiat Serv, Vet Affairs San Diego Healthcare Syst, San Diego, CA USA

[23] Inc, 23andMe, Sunnyvale, CA USA

[24] Leiden Univ, Med Ctr, Dept Neurol, , Zuid Holland, Leiden, Netherlands

[25] Feinstein Inst Med Res, Northwell Hlth, Manhasset, NY USA

[26] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Zuid Holland, Netherlands

[27] German Ctr Mental Hlth DZPG, Partner Site Berlin Potsdam, Berlin, Germany

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

关键词：

ASSOCIATION ANALYSES; RISK LOCI; GENOTYPE IMPUTATION; SUSCEPTIBILITY LOCI; IDENTIFY; COMPLEMENT; HAPLOTYPE; VARIANTS; DISEASES; BIOBANK;

D O I：

10.1038/s41467-024-53595-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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共 50 条

[41] Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease [J].

Winkler, Thomas W. ;

Grassmann, Felix ;

Brandl, Caroline ;

Kiel, Christina ;

Guenther, Felix ;

Strunz, Tobias ;

Weidner, Lorraine ;

Zimmermann, Martina E. ;

Korb, Christina A. ;

Poplawski, Alicia ;

Schuster, Alexander K. ;

Mueller-Nurasyid, Martina ;

Peters, Annette ;

Rauscher, Franziska G. ;

Elze, Tobias ;

Horn, Katrin ;

Scholz, Markus ;

Canadas-Garre, Marisa ;

McKnight, Amy Jayne ;

Quinn, Nicola ;

Hogg, Ruth E. ;

Kuechenhoff, Helmut ;

Heid, Iris M. ;

Stark, Klaus J. ;

Weber, Bernhard H. F. .

BMC MEDICAL GENOMICS, 2020, 13 (01)

[42] Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies [J].

Nalls, Mike A. ;

Blauwendraat, Cornelis ;

Vallerga, Costanza L. ;

Heilbron, Karl ;

Bandres-Ciga, Sara ;

Chang, Diana ;

Tan, Manuela ;

Kia, Demis A. ;

Noyce, Alastair J. ;

Xue, Angli ;

Bras, Jose ;

Young, Emily ;

von Coelln, Rainer ;

Simon-Sanchez, Javier ;

Schulte, Claudia ;

Sharma, Manu ;

Krohn, Lynne ;

Pihlstrom, Lasse ;

Siitonen, Ari ;

Iwaki, Hirotaka ;

Leonard, Hampton ;

Faghri, Faraz ;

Gibbs, J. Raphael ;

Hernandez, Dena G. ;

Scholz, Sonja W. ;

Botia, Juan A. ;

Martinez, Maria ;

Corvol, Jean-Christophe ;

Lesage, Suzanne ;

Jankovic, Joseph ;

Shulman, Lisa M. ;

Sutherland, Margaret ;

Tienari, Pentti ;

Majamaa, Kari ;

Toft, Mathias ;

Andreassen, Ole A. ;

Bangale, Tushar ;

Brice, Alexis ;

Yang, Jian ;

Gan-Or, Ziv ;

Gasser, Thomas ;

Heutink, Peter ;

Shulman, Joshua M. ;

Wood, Nicholas W. ;

Hinds, David A. ;

Hardy, John A. ;

Morris, Huw R. ;

Gratten, Jacob ;

Visscher, Peter M. ;

Graham, Robert R. .

LANCET NEUROLOGY, 2019, 18 (12) :1091-1102

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Han, Xikun ;

Gharahkhani, Puya ;

Mitchell, Paul ;

Liew, Gerald ;

Hewitt, Alex W. ;

MacGregor, Stuart .

JOURNAL OF HUMAN GENETICS, 2020, 65 (08) :657-665

[44] Natural resistance to Meningococcal Disease related to CFH loci: Meta-analysis of genome-wide association studies [J].

Martinon-Torres, Federico ;

Png, Eileen ;

Khor, Chiea Chuen ;

Davila, Sonia ;

Wright, Victoria J. ;

Sim, Kar Seng ;

Vega, Ana ;

Fachal, Laura ;

Inwald, David ;

Nadel, Simon ;

Carrol, Enitan D. ;

Martinon-Torres, Nazareth ;

Marcos Alonso, Sonia ;

Carracedo, Angel ;

Morteruel, Elvira ;

Lopez-Bayon, Julio ;

Concha Torre, Andres ;

Calvo Monge, Cristina ;

Gonzalez de Aguilar, Pilar Azcon ;

Esteban Torne, Elisabeth ;

del Carmen Martinez-Padilla, Maria ;

Maria Martinon-Sanchez, Jose ;

Levin, Michael ;

Hibberd, Martin L. ;

Salas, Antonio .

SCIENTIFIC REPORTS, 2016, 6

[45] A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium [J].

Soranzo, Nicole ;

Spector, Tim D. ;

Mangino, Massimo ;

Kuehnel, Brigitte ;

Rendon, Augusto ;

Teumer, Alexander ;

Willenborg, Christina ;

Wright, Benjamin ;

Chen, Li ;

Li, Mingyao ;

Salo, Perttu ;

Voight, Benjamin F. ;

Burns, Philippa ;

Laskowski, Roman A. ;

Xue, Yali ;

Menzel, Stephan ;

Altshuler, David ;

Bradley, John R. ;

Bumpstead, Suzannah ;

Burnett, Mary-Susan ;

Devaney, Joseph ;

Doering, Angela ;

Elosua, Roberto ;

Epstein, Stephen E. ;

Erber, Wendy ;

Falchi, Mario ;

Garner, Stephen F. ;

Ghori, Mohammed J. R. ;

Goodall, Alison H. ;

Gwilliam, Rhian ;

Hakonarson, Hakon H. ;

Hall, Alistair S. ;

Hammond, Naomi ;

Hengstenberg, Christian ;

Illig, Thomas ;

Koenig, Inke R. ;

Knouff, Christopher W. ;

McPherson, Ruth ;

Melander, Olle ;

Mooser, Vincent ;

Nauck, Matthias ;

Nieminen, Markku S. ;

O'Donnell, Christopher J. ;

Peltonen, Leena ;

Potter, Simon C. ;

Prokisch, Holger ;

Rader, Daniel J. ;

Rice, Catherine M. ;

Roberts, Robert ;

Salomaa, Veikko .

NATURE GENETICS, 2009, 41 (11) :1182-U38

[46] Large meta-analysis of genome-wide association studies identifies five loci for lean body mass [J].

Zillikens, M. Carola ;

Demissie, Serkalem ;

Hsu, Yi-Hsiang ;

Yerges-Armstrong, Laura M. ;

Chou, Wen-Chi ;

Stolk, Lisette ;

Livshits, Gregory ;

Broer, Linda ;

Johnson, Toby ;

Koller, Daniel L. ;

Kutalik, Zoltÿn ;

Luan, Jian'an ;

Malkin, Ida ;

Ried, Janina S. ;

Smith, Albert V. ;

Thorleifsson, Gudmar ;

Vandenput, Liesbeth ;

Zhao, Jing Hua ;

Zhang, Weihua ;

Aghdassi, Ali ;

Akesson, Kristina ;

Amin, Najaf ;

Baier, Leslie J. ;

Barroso, Ines ;

Bennett, David A. ;

Bertram, Lars ;

Biffar, Rainer ;

Bochud, Murielle ;

Boehnke, Michael ;

Borecki, Ingrid B. ;

Buchman, Aron S. ;

Byberg, Liisa ;

Campbell, Harry ;

Obanda, Natalia Campos ;

Cauley, Jane A. ;

Cawthon, Peggy M. ;

Cederberg, Henna ;

Chen, Zhao ;

Cho, Nam H. ;

Choi, Hyung Jin ;

Claussnitzer, Melina ;

Collins, Francis ;

Cummings, Steven R. ;

De Jager, Philip L. ;

Demuth, Ilja ;

Dhonukshe-Rutten, Rosalie A. M. ;

Diatchenko, Luda ;

Eiriksdottir, Gudny ;

Enneman, Anke W. ;

Erdos, Mike .

NATURE COMMUNICATIONS, 2017, 8

[47] A Meta-Analysis of the Genome-Wide Association Studies on Two Genetically Correlated Phenotypes Suggests Four New Risk Loci for Headaches [J].

Meng, Weihua ;

Reel, Parminder S. ;

Nangia, Charvi ;

Rajendrakumar, Aravind Lathika ;

Hebert, Harry L. ;

Guo, Qian ;

Adams, Mark J. ;

Zheng, Hua ;

Lu, Zen Haut ;

Ray, Debashree ;

Colvin, Lesley A. ;

Palmer, Colin N. A. ;

Mcintosh, Andrew M. ;

Smith, Blair H. .

PHENOMICS, 2023, 3 (01) :64-76

[48] Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus [J].

Morris, David L. ;

Sheng, Yujun ;

Zhang, Yan ;

Wang, Yong-Fei ;

Zhu, Zhengwei ;

Tombleson, Philip ;

Chen, Lingyan ;

Graham, Deborah S. Cunninghame ;

Bentham, James ;

Roberts, Amy L. ;

Chen, Ruoyan ;

Zuo, Xianbo ;

Wang, Tingyou ;

Wen, Leilei ;

Yang, Chao ;

Liu, Lu ;

Yang, Lulu ;

Li, Feng ;

Huang, Yuanbo ;

Yin, Xianyong ;

Yang, Sen ;

Rnnblom, Lars ;

Furnrohr, Barbara G. ;

Voll, Reinhard E. ;

Schett, Georg ;

Costedoat-Chalumeau, Nathalie ;

Gaffney, Patrick M. ;

Lau, Yu Lung ;

Zhang, Xuejun ;

Yang, Wanling ;

Cui, Yong ;

Vyse, Timothy J. .

NATURE GENETICS, 2016, 48 (08) :940-+

[49] Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture [J].

Estrada, Karol ;

Styrkarsdottir, Unnur ;

Evangelou, Evangelos ;

Hsu, Yi-Hsiang ;

Duncan, Emma L. ;

Ntzani, Evangelia E. ;

Oei, Ling ;

Albagha, Omar M. E. ;

Amin, Najaf ;

Kemp, John P. ;

Koller, Daniel L. ;

Li, Guo ;

Liu, Ching-Ti ;

Minster, Ryan L. ;

Moayyeri, Alireza ;

Vandenput, Liesbeth ;

Willner, Dana ;

Xiao, Su-Mei ;

Yerges-Armstrong, Laura M. ;

Zheng, Hou-Feng ;

Alonso, Nerea ;

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