Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis

abstract: ...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=510 32 310 10 ), with heterogeneity detected only at the PSMB9/TAP1 locus (I 2 =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=2.510 4 ). A sevenSNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r=0.30, P=310 128 ). This model paralleled the known EastWest gradient in disease risk. Moreover, the prediction of a SouthNorth axis was confirmed by registry data showing that the prevalence of IgANattributable 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.

... 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

... cases and 902 controls) were recruited in Beijing, China and were comprised of individuals of Han Chinese ancestry. The most associated SNPs were then followed up in additional cohorts of Han Chinese and Europeans (1,950 cases and 1,920 controls). In the combined analysis, we discovered 5 novel susceptibility loci with consistent effects across individual cohorts. These include 3 distinct intervals in the MHC-II region on chromosome 6p21, with the strongest signal encompassing the HLA DQB1/DQA1/DRB1 locus (abbreviated as DQB1/DRB1 hereafter). Imputation of classical alleles suggested that this signal was partially conveyed by a strong protective effect of the DRB1*1501-DQB1*0602 haplotype. The second signal on Chr. 6p21 encompassed a 100 Kb region containing TAP2, TAP1, PSMB8 , and PSMB9 genes ( TAP2/PSMB9 locus) and the third signal on Chr. 6p21 contained the HLA DPA1/DPB1/DPB2 genes ( DPA1/DPB2 locus). Independence of these three regions on Chr. 6p21 was demonstrated by their localization

... 0.83 (0.780.90) 4.810 7 6p21 HLA-DPB2, -DPB1, -DPA1 rs2412971 (A) 0.28592 0.75 (0.700.81) 2.310 15 22q12 HORMAD2, MTMR3, LIF, OSM, GATSL3, SF3A1 rs6677604 (A)* rs2412971 (A) 0.23171 1.26 (1.121.43) 2.210 4 1q32 by 22q12 interaction term This model represents the solution of a stepwise logistic regression algorithm (BIC-based stepwise model selection). The coefficients from this model are used to refine the risk score for IgAN. First-Order Interaction Screen Reveals Significant

...). 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=2.510 4 ). A sevenSNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r=0.30, P=310 128 ). This

... susceptibility loci for this trait. In this paper, we study the largest IgAN case-control cohort reported to date, composed of 10,775 individuals of European, Asian, and African-American ancestry. We confirm that all five loci are significant contributors to disease risk across this multi-ethnic cohort. In addition, we identify two novel independent susceptibility alleles within the HLA-DQB1/DRB1 locus and a new genetic interaction between loci on Chr.1p36 and Chr.22q22. We develop a sevenSNP genetic risk

... controls, described in Table S1 ). While each individual cohort at best had 4050% power to replicate original GWAS findings, the combined replication cohort (2,228 cases and 2,561 controls) provided essentially 100% power for replication across the range of allele frequencies and odds ratios initially observed ( Table S2 ). We genotyped the two top-scoring SNPs for the CFHR3/R1 , TAP2/PSMB9 , DPA1/DPB2 , and HORMAD2 loci, but four SNPs were included for the DQB1/DRB1 locus to test for independent

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Gene: HLA-DPB2 - major histocompatibility complex, class II, DP beta 2 (pseudogene) - (NCBI)

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