作者
Huan Liu,Atlas Khan,Elena Sánchez-Rodríguez,Francesca Zanoni,Yifu Li,Nicholas J. 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 R. Crosslin,Thomas Rauen,Jürgen Floege,Frank Eitner,Zina Moldoveanu,Colin Reily,Barbora Knoppová,Stacy Hall,Justin T. Sheff,Bruce A. Julian,Robert Wyatt,Hitoshi Suzuki,Jingyuan Xie,Nan Chen,Xu‐Jie 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 Novák,Ali G. Gharavi,Krzysztof Kiryluk
摘要
Abstract Immunoglobulin 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.