RT Journal Article SR Electronic T1 GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway JF bioRxiv FD Cold Spring Harbor Laboratory SP 076414 DO 10.1101/076414 A1 Krzysztof Kiryluk A1 Yifu Li A1 Zina Moldoveanu A1 Hitoshi Suzuki A1 Colin Reily A1 Ping Hou A1 Jingyuan Xie A1 Nikol Mladkova A1 Sindhuri Prakash A1 Clara Fischman A1 Samantha Shapiro A1 Robert A. LeDesma A1 Drew Bradbury A1 Iuliana Ionita-Laza A1 Frank Eitner A1 Thomas Rauen A1 Nicolas Maillard A1 Francois Berthoux A1 Jürgen Floege A1 Nan Chen A1 Hong Zhang A1 Francesco Scolari A1 Robert J. Wyatt A1 Bruce A. Julian A1 Ali G. Gharavi A1 Jan Novak YR 2016 UL http://biorxiv.org/content/early/2016/09/21/076414.abstract AB 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 × 10−11) and C1GALT1C1 (rs5910940, P = 2.7 × 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.Author Summary O-glycosylation is a common type of post-translational modification of proteins; specific abnormalities in the mechanism of O-glycosylation have been implicated in cancer, inflammatory and blood diseases. However, the molecular basis of abnormal O-glycosylation in these complex disorders is not known. We studied the genetic basis of defective O-glycosylation of serum Immunoglobulin A1 (IgA1), which represents the key pathogenic defect in IgA nephropathy, the most common form of primary glomerulonephritis worldwide. We report our results of the first genome-wide association study for this trait using serum assays in 2,633 individuals of European and East Asian ancestry. In our genome scan, we observed two significant signals with large effects, on chromosomes 7p21.3 and Xq24, jointly explaining about 7% of trait variability. These signals implicate two genes that encode molecular partners essential for enzymatic O-glycosylation of IgA1 and mucins, and represent potential new targets for therapy.