Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.
IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹⁰), with heterogeneity detected only at the PSMB9/TAP1 locus (I² = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻⁴). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²⁸). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
Krzysztof
K
Kiryluk
Yifu
Y
Li
Simone
S
Sanna-Cherchi
Mersedeh
M
Rohanizadegan
Hitoshi
H
Suzuki
Frank
F
Eitner
Holly J
HJ
Snyder
Murim
M
Choi
Ping
P
Hou
Francesco
F
Scolari
Claudia
C
Izzi
Maddalena
M
Gigante
Loreto
L
Gesualdo
Silvana
S
Savoldi
Antonio
A
Amoroso
Daniele
D
Cusi
Pasquale
P
Zamboli
Bruce A
BA
Julian
Jan
J
Novak
Robert J
RJ
Wyatt
Krzysztof
K
Mucha
Markus
M
Perola
Kati
K
Kristiansson
Alexander
A
Viktorin
Patrik K
PK
Magnusson
Gudmar
G
Thorleifsson
Unnur
U
Thorsteinsdottir
Kari
K
Stefansson
Anne
A
Boland
Marie
M
Metzger
Lise
L
Thibaudin
Christoph
C
Wanner
Kitty J
KJ
Jager
Shin
S
Goto
Dita
D
Maixnerova
Hussein H
HH
Karnib
Judit
J
Nagy
Ulf
U
Panzer
Jingyuan
J
Xie
Nan
N
Chen
Vladimir
V
Tesar
Ichiei
I
Narita
Francois
F
Berthoux
Jürgen
J
Floege
Benedicte
B
Stengel
Hong
H
Zhang
Richard P
RP
Lifton
Ali G
AG
Gharavi
D000349:Africa; D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001208:Asia; D044466:Asian People / Q000235:genetics; D001798:Blood Proteins / Q000235:genetics*; D015331:Cohort Studies; D003546:Cysteine Endopeptidases / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D005060:Europe; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005922:Glomerulonephritis, IGA / Q000235:genetics*; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
D001798:Blood Proteins; C105970:CFHR3 protein, human; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C071313:LMP-2 protein; D003546:Cysteine Endopeptidases