Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits

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. Hebbring, John B. Harley, Halima Moncrieffe, Leah C. Kottyan, Bahram Namjou-Khales, Theresa L. Walunas, Rachel Knevel, Soumya Raychaudhuri, Elizabeth W. Karlson, Joshua C. Denny, Ian B. Stanaway, David Crosslin, Thomas Rauen, Jürgen Floege, Frank Eitner, Zina Moldoveanu, Colin Reily, Barbora Knoppova, Stacy Hall, Justin T. Sheff, Bruce A. Julian, Robert J. Wyatt, Hitoshi Suzuki, Jingyuan Xie, Nan Chen, Xujie Zhou, Hong Zhang, Lennart Hammarström, Alexander Viktorin, Patrik K. E. Magnusson, Ning Shang, George Hripcsak, Chunhua Weng, Tatjana Rundek, Mitchell S. V. Elkind, Elizabeth C. Oelsner, R. Graham Barr, Iuliana Ionita-Laza, Jan Novak, Ali G. Gharavi and Krzysztof Kiryluk ()
Additional contact information
Lili Liu: Columbia University
Atlas Khan: Columbia University
Elena Sanchez-Rodriguez: Columbia University
Francesca Zanoni: Columbia University
Yifu Li: Columbia University
Nicholas Steers: Columbia University
Olivia Balderes: Columbia University
Junying Zhang: Columbia University
Priya Krithivasan: Columbia University
Robert A. LeDesma: Princeton University
Clara Fischman: University of Pennsylvania
Scott J. Hebbring: Marshfield Clinic Research Institute
John B. Harley: Cincinnati Children’s Hospital
Halima Moncrieffe: Cincinnati Children’s Hospital
Leah C. Kottyan: Cincinnati Children’s Hospital
Bahram Namjou-Khales: Cincinnati Children’s Hospital
Theresa L. Walunas: Northwestern University Feinberg School of Medicine
Rachel Knevel: Brigham and Women’s Hospital and Harvard Medical School
Soumya Raychaudhuri: Brigham and Women’s Hospital and Harvard Medical School
Elizabeth W. Karlson: Brigham and Women’s Hospital and Harvard Medical School
Joshua C. Denny: Vanderbilt University School of Medicine
Ian B. Stanaway: University of Washington
David Crosslin: University of Washington
Thomas Rauen: RWTH University of Aachen
Jürgen Floege: RWTH University of Aachen
Frank Eitner: RWTH University of Aachen
Zina Moldoveanu: University of Alabama at Birmingham
Colin Reily: University of Alabama at Birmingham
Barbora Knoppova: University of Alabama at Birmingham
Stacy Hall: University of Alabama at Birmingham
Justin T. Sheff: University of Alabama at Birmingham
Bruce A. Julian: University of Alabama at Birmingham
Robert J. Wyatt: University of Tennessee Health Sciences Center
Hitoshi Suzuki: Juntendo University Faculty of Medicine
Jingyuan Xie: Shanghai Jiao Tong University School of Medicine
Nan Chen: Shanghai Jiao Tong University School of Medicine
Xujie Zhou: Peking University First Hospital, Peking University Institute of Nephrology
Hong Zhang: Peking University First Hospital, Peking University Institute of Nephrology
Lennart Hammarström: Karolinska Institutet
Alexander Viktorin: Karolinska Institutet
Patrik K. E. Magnusson: Karolinska Institutet
Ning Shang: Columbia University
George Hripcsak: Columbia University
Chunhua Weng: Columbia University
Tatjana Rundek: University of Miami
Mitchell S. V. Elkind: Columbia University
Elizabeth C. Oelsner: Columbia University
R. Graham Barr: Columbia University
Iuliana Ionita-Laza: Columbia University
Jan Novak: University of Alabama at Birmingham
Ali G. Gharavi: Columbia University
Krzysztof Kiryluk: Columbia University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.

Date: 2022
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DOI: 10.1038/s41467-022-34456-6

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