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

Author

Listed:
  • 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
    University of Cincinnati College of Medicine
    US Department of Veterans Affairs Medical Center)

  • Halima Moncrieffe

    (Cincinnati Children’s Hospital
    University of Cincinnati College of Medicine)

  • Leah C. Kottyan

    (Cincinnati Children’s Hospital
    University of Cincinnati College of Medicine)

  • Bahram Namjou-Khales

    (Cincinnati Children’s Hospital
    University of Cincinnati College of Medicine)

  • 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
    Bayer Pharma AG)

  • 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
    University of Miami)

  • Mitchell S. V. Elkind

    (Columbia University)

  • Elizabeth C. Oelsner

    (Columbia University)

  • R. Graham Barr

    (Columbia University
    Columbia University)

  • Iuliana Ionita-Laza

    (Columbia University)

  • Jan Novak

    (University of Alabama at Birmingham)

  • Ali G. Gharavi

    (Columbia University)

  • Krzysztof Kiryluk

    (Columbia University)

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.

Suggested Citation

  • 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. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34456-6
    DOI: 10.1038/s41467-022-34456-6
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