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. KarlsonJoshua 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, Krzysztof Kiryluk

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Article number6859
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

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