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

• Published in: Nature communications 2022-11, Vol.13 (1), p.6859-17, Article 6859
• Main Authors: Liu, Lili, Khan, Atlas, Sanchez-Rodriguez, Elena, Zanoni, Francesca, Li, Yifu, Steers, Nicholas, Balderes, Olivia, Zhang, Junying, Krithivasan, Priya, LeDesma, Robert A., Fischman, Clara, Hebbring, Scott J., Harley, John B., Moncrieffe, Halima, Kottyan, Leah C., Namjou-Khales, Bahram, Walunas, Theresa L., Knevel, Rachel, Raychaudhuri, Soumya, Karlson, Elizabeth W., Denny, Joshua C., Stanaway, Ian B., Crosslin, David, Rauen, Thomas, Floege, Jürgen, Eitner, Frank, Moldoveanu, Zina, Reily, Colin, Knoppova, Barbora, Hall, Stacy, Sheff, Justin T., Julian, Bruce A., Wyatt, Robert J., Suzuki, Hitoshi, Xie, Jingyuan, Chen, Nan, Zhou, Xujie, Zhang, Hong, Hammarström, Lennart, Viktorin, Alexander, Magnusson, Patrik K. E., Shang, Ning, Hripcsak, George, Weng, Chunhua, Rundek, Tatjana, Elkind, Mitchell S. V., Oelsner, Elizabeth C., Barr, R. Graham, Ionita-Laza, Iuliana, Novak, Jan, Gharavi, Ali G., Kiryluk, Krzysztof
• Format: Article
• Language: English
• Subjects: 45; 45/43; 631/208/205/2138; 631/250/347; 692/4022/1585/2759/1522; Abnormalities; Animals; Antigens; Autoimmune diseases; Body mass index; Body size; Celiac disease; Celiac Disease - genetics; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Gene expression; Gene frequency; Genes; Genetic engineering; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glomerulonephritis, IGA - complications; Glomerulonephritis, IGA - genetics; Humanities and Social Sciences; Humans; IgA nephropathy; Immunoglobulin A; Immunoglobulin A - genetics; Immunoglobulins; Infectious diseases; Inflammatory bowel disease; Inflammatory Bowel Diseases; Inflammatory diseases; Intestine; Kidney - metabolism; Kidneys; Localization; Medicin och hälsovetenskap; Mice; Microbiomes; Mucosa; multidisciplinary; Quantitative trait loci; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34456-6

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. Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.