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 = 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.

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

“…In a recent GWAS replication study, the association of 1q32 with IgAN susceptibility was confirmed in eight new independent cohorts. 29 On the basis of this genetic association, we further explored the clinical significance of rs6677604 in IgAN. Our finding that the rs6677604 locus was associated with mesangial C3 deposition in IgAN implied a functional role for rs6677604 in complement activation and more importantly, aroused our interest in the complement activation mechanism in IgAN.…”

Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease

“…We manually curated a list of SNPs that both passed genome-wide significance and were associated with kidney disease traits (Table S7). [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] To acquire independent loci, we removed any SNPs having r 2 R 0.2. In total, we analyzed 110 leading SNPs and 2,357 tagging SNPs with r 2 R 0.8 (Table S7).…”

IgA1 Glycosylation Is Heritable in Healthy Twins

“…[5][6][7][8][9] The incidence of IgAN varies geographically, being most prevalent in East Asian populations and less prevalent in European and African populations. 10,11 Six genomewide association studies have collectively identified 20 distinct loci associated with IgAN. Interestingly, most of these loci are shared with other immune-related diseases.…”