Author:
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
Abstract
AbstractImmunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and has a known role in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed genetic analyses of serum IgA levels in 41,263 individuals of diverse ancestries. We observed unexpected variability in IgA levels across major ancestral populations, with African ancestry being reproducibly associated with higher serum IgA levels compared to other ancestries. The trans-ethnic GWAS analysis identified 20 genome-wide significant loci associated with serum IgA levels, including nine known and 11 novel loci. Systematic co-localization analysis with blood and primary immune cell expression QTLs prioritized candidate genes for 14 of 20 loci. Most GWAS loci encoded genes that produce immune defects and IgA abnormalities when genetically manipulated in mice. We uncovered positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes and body mass index, as well as negative genetic correlations with celiac disease, inflammatory bowel disease, several infections, and intestinal microbiome diversity. Our findings provide novel insights into the genetic regulation of IgA production and its potential role in human disease.
Publisher
Cold Spring Harbor Laboratory