title: GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.
abstract: 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 that 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.
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kiryluk
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Yifu
authors.identifier: 0000-0002-7077-7689
authors.initials: Y
authors.lastname: Li
authors.affiliation: Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Zina
authors.initials: Z
authors.lastname: Moldoveanu
authors.affiliation: Division of Nephrology, Dept. of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Dept. of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Colin
authors.initials: C
authors.lastname: Reily
authors.affiliation: Renal Div., Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Dept. of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Xie
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Nikol
authors.initials: N
authors.lastname: Mladkova
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Sindhuri
authors.initials: S
authors.lastname: Prakash
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Clara
authors.initials: C
authors.lastname: Fischman
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Shapiro
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Robert A
authors.identifier: 0000-0003-1435-4523
authors.initials: RA
authors.lastname: LeDesma
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Drew
authors.initials: D
authors.lastname: Bradbury
authors.affiliation: Dept. of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, United States of America.
authors.forename: Iuliana
authors.initials: I
authors.lastname: Ionita-Laza
authors.affiliation: Dept. of Nephrology, RWTH University of Aachen, Aachen, Germany.|Kidney Diseases Research, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.affiliation: Dept. of Nephrology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.affiliation: Nephrology, Dialysis, and Renal Transplantation Dept., University North Hospital, Saint Etienne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Maillard
authors.affiliation: Nephrology, Dialysis, and Renal Transplantation Dept., University North Hospital, Saint Etienne, France.
authors.forename: Francois
authors.identifier: 0000-0003-3816-8901
authors.initials: F
authors.lastname: Berthoux
authors.affiliation: Dept. of Nephrology, RWTH University of Aachen, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Dept. of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Renal Div., Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Div. of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, Univ of Brescia, Brescia, Italy.|Dept. of Medical and Surgical Specialties, Radiological Sciences, University of Brescia, Brescia, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.affiliation: Div. of Pediatric Nephrology, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States of America.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wyatt
authors.affiliation: Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.|Dept. of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.affiliation: Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: Dept. of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D002460:Cell Line; D015331:Cohort Studies; D005690:Galactose / Q000172:deficiency; D005700:Galactosyltransferases / Q000235:genetics*; D005786:Gene Expression Regulation; D005787:Gene Frequency; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D005922:Glomerulonephritis, IGA / Q000097:blood / Q000208:ethnology / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D008957:Models, Genetic; D018832:Molecular Chaperones / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: C505369:C1GALT1C1 protein, human; D007070:Immunoglobulin A; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C485367:HECW1 protein, human; D044767:Ubiquitin-Protein Ligases; C505293:C1GALT1 protein, human; D005700:Galactosyltransferases; D005690:Galactose