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

共 50 条

[21] Genome-wide meta-analysis reveals novel susceptibility loci for thyrotoxic periodic paralysis [J].

Li, Gloria Hoi-Yee ;

Cheung, Ching-Lung ;

Zhao, Shuang-Xia ;

Song, Huai-Dong ;

Kung, Annie Wai-Chee .

EUROPEAN JOURNAL OF ENDOCRINOLOGY, 2020, 183 (06) :607-617

[22] Meta-analysis of genome-wide association data identifies novel susceptibility loci for obesity [J].

Pei, Yu-Fang ;

Zhang, Lei ;

Liu, Yongjun ;

Li, Jian ;

Shen, Hui ;

Liu, Yao-Zhong ;

Tian, Qing ;

He, Hao ;

Wu, Shuyan ;

Ran, Shu ;

Han, Yingying ;

Hai, Rong ;

Lin, Yong ;

Zhu, Jingying ;

Zhu, Xue-Zhen ;

Papasian, Christopher J. ;

Deng, Hong-Wen .

HUMAN MOLECULAR GENETICS, 2014, 23 (03) :820-830

[23] Meta-analysis of genome-wide associations and polygenic risk prediction for atrial fibrillation in more than 180,000 cases [J].

Roselli, Carolina ;

Surakka, Ida ;

Olesen, Morten S. ;

Sveinbjornsson, Gardar ;

Marston, Nicholas A. ;

Choi, Seung Hoan ;

Holm, Hilma ;

Chaffin, Mark ;

Gudbjartsson, Daniel ;

Hill, Matthew C. ;

Aegisdottir, Hildur ;

Albert, Christine M. ;

Alonso, Alvaro ;

Anderson, Christopher D. ;

Arking, Dan E. ;

Arnar, David O. ;

Barnard, John ;

Benjamin, Emelia J. ;

Braunwald, Eugene ;

Brumpton, Ben ;

Campbell, Archie ;

Chami, Nathalie ;

Chasman, Daniel I. ;

Cho, Kelly ;

Choi, Eue-Keun ;

Christophersen, Ingrid E. ;

Chung, Mina K. ;

Conen, David ;

Crijns, Harry J. ;

Cutler, Michael J. ;

Czuba, Tomasz ;

Damrauer, Scott M. ;

Dichgans, Martin ;

Doerr, Marcus ;

Dudink, Elton ;

Duong, ThuyVy ;

Erikstrup, Christian ;

Esko, Tnu ;

Fatkin, Diane ;

Faul, Jessica D. ;

Ferreira, Manuel ;

Freitag, Daniel F. ;

Ganesh, Santhi K. ;

Gaziano, J. Michael ;

Geelhoed, Bastiaan ;

Ghouse, Jonas ;

Gieger, Christian ;

Giulianini, Franco ;

Graham, Sarah E. ;

Gudnason, Vilmundur .

NATURE GENETICS, 2025, :539-547

[24] A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci [J].

Chang, Diana ;

Nalls, Mike A. ;

Hallgrimsdottir, Ingileif B. ;

Hunkapiller, Julie ;

van der Brug, Marcel ;

Cai, Fang ;

Kerchner, Geoffrey A. ;

Ayalon, Gai ;

Bingol, Baris ;

Sheng, Morgan ;

Hinds, David ;

Behrens, Timothy W. ;

Singleton, Andrew B. ;

Bhangale, Tushar R. ;

Graham, Robert R. .

NATURE GENETICS, 2017, 49 (10) :1511-+

[25] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk [J].

Jansen, Iris E. ;

Savage, Jeanne E. ;

Watanabe, Kyoko ;

Bryois, Julien ;

Williams, Dylan M. ;

Steinberg, Stacy ;

Sealock, Julia ;

Karlsson, Ida K. ;

Hagg, Sara ;

Athanasiu, Lavinia ;

Voyle, Nicola ;

Proitsi, Petroula ;

Witoelar, Aree ;

Stringer, Sven ;

Aarsland, Dag ;

Almdahl, Ina S. ;

Andersen, Fred ;

Bergh, Sverre ;

Bettella, Francesco ;

Bjornsson, Sigurbjorn ;

Braekhus, Anne ;

Brathen, Geir ;

de Leeuw, Christiaan ;

Desikan, Rahul S. ;

Djurovic, Srdjan ;

Dumitrescu, Logan ;

Fladby, Tormod ;

Hohman, Timothy J. ;

Jonsson, Palmi, V ;

Kiddle, Steven J. ;

Rongve, Arvid ;

Saltvedt, Ingvild ;

Sando, Sigrid B. ;

Selbaek, Geir ;

Shoai, Maryam ;

Skene, Nathan G. ;

Snaedal, Jon ;

Stordal, Eystein ;

Ulstein, Ingun D. ;

Wang, Yunpeng ;

White, Linda R. ;

Hardy, John ;

Hjerling-Leffler, Jens ;

Sullivan, Patrick F. ;

van der Flier, Wiesje M. ;

Dobson, Richard ;

Davis, Lea K. ;

Stefansson, Hreinn ;

Stefansson, Kari ;

Pedersen, Nancy L. .

NATURE GENETICS, 2019, 51 (03) :404-+

[26] Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity [J].

Hagg, Sara ;

Ganna, Andrea ;

Van der Laan, Sander W. ;

Esko, Tonu ;

Pers, Tune H. ;

Locke, Adam E. ;

Berndt, Sonja I. ;

Justice, Anne E. ;

Kahali, Bratati ;

Siemelink, Marten A. ;

Pasterkamp, Gerard ;

Strachan, David P. ;

Speliotes, Elizabeth K. ;

North, Kari E. ;

Loos, Ruth J. F. ;

Hirschhorn, Joel N. ;

Pawitan, Yudi ;

Ingelsson, Erik .

HUMAN MOLECULAR GENETICS, 2015, 24 (23) :6849-6860

[27] Genome-Wide Meta-analysis Identifies Risk Loci and Improves Disease Prediction of Age-Related Macular Degeneration [J].

He, Weixiong ;

Han, Xikun ;

Ong, Jue-Sheng ;

Wu, Yeda ;

Hewitt, Alex W. ;

Mackey, David A. ;

Gharahkhani, Puya ;

Macgregor, Stuart .

OPHTHALMOLOGY, 2024, 131 (01) :16-29

[28] Meta-analysis methods for genome-wide association studies and beyond [J].

Evangelou, Evangelos ;

Ioannidis, John P. A. .

NATURE REVIEWS GENETICS, 2013, 14 (06) :379-389

[29] Meta-Analysis of Genome-wide Association Studies with Overlapping Subjects [J].

Lin, Dan-Yu ;

Sullivan, Patrick F. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 85 (06) :862-872

[30] Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction [J].

Conti, David, V ;

Darst, Burcu F. ;

Moss, Lilit C. ;

Saunders, Edward J. ;

Sheng, Xin ;

Chou, Alisha ;

Schumacher, Fredrick R. ;

Al Olama, Ali Amin ;

Benlloch, Sara ;

Dadaev, Tokhir ;

Brook, Mark N. ;

Sahimi, Ali ;

Hoffmann, Thomas J. ;

Takahashi, Atushi ;

Matsuda, Koichi ;

Momozawa, Yukihide ;

Fujita, Masashi ;

Muir, Kenneth ;

Lophatananon, Artitaya ;

Wan, Peggy ;

Le Marchand, Loic ;

Wilkens, Lynne R. ;

Stevens, Victoria L. ;

Gapstur, Susan M. ;

Carter, Brian D. ;

Schleutker, Johanna ;

Tammela, Teuvo L. J. ;

Sipeky, Csilla ;

Auvinen, Anssi ;

Giles, Graham G. ;

Southey, Melissa C. ;

MacInnis, Robert J. ;

Cybulski, Cezary ;

Wokolorczyk, Dominika ;

Lubinski, Jan ;

Neal, David E. ;

Donovan, Jenny L. ;

Hamdy, Freddie C. ;

Martin, Richard M. ;

Nordestgaard, Borge G. ;

Nielsen, Sune F. ;

Weischer, Maren ;

Bojesen, Stig E. ;

Roder, Martin Andreas ;

Iversen, Peter ;

Batra, Jyotsna ;

Chambers, Suzanne ;

Moya, Leire ;

Horvath, Lisa ;

Clements, Judith A. .

NATURE GENETICS, 2021, 53 (01) :11-15

← 1 2 3 4 5 →