Included in eqtl, genomewide_association themes

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GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway

Created on 21st September 2016

Krzysztof Kiryluk; Yifu Li; Zina Moldoveanu; Hitoshi Suzuki; Colin Reily; Ping Hou; Jingyuan Xie; Nikol Mladkova; Sindhuri Prakash; Clara Fischman; Samantha Shapiro; Robert A. LeDesma; Drew Bradbury; Iuliana Ionita-Laza; Frank Eitner; Thomas Rauen; Nicolas Maillard; Francois Berthoux; Jurgen Floege; Nan Chen; Hong Zhang; Francesco Scolari; Robert J. Wyatt; Bruce A. Julian; Ali G. Gharavi; Jan Novak;

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1, which encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

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