A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy

Abstract

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

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).…”

Genome-wide scan identifies a copy number variable region at 3p21.1 that influences the TLR9 expression levels in IgA nephropathy patients

“…Many LGWS and GWAS in both familial and sporadic IgAN suggest that there is a strong genetic component in the disease. [7][8][9][10][11][12] However, most studies have not evaluated the contribution to this complex disorder of other forms of genetic variation, such as structural variations, mainly in the form of CNVs. 15 Indeed, CNVs have recently been shown to have an important role in complex disease phenotypes as psoriasis, 30 rheumatoid arthritis 31 and systemic lupus erythematosus.…”

“…)del, containing the COL11A2 (collagen, type XI, alpha 2 isoform 1), were found in very close proximity to SNPs that gave multiple associations in the MHC class I region and HLA complex group genes identified by three independent GWAS. [10][11][12] Moreover, the loss chr6.hg18:g.(?_134 801-335)_(134 848 458_? )del overlapped with the region named IGAN1 identified in a GWLS.…”

“…Three GWLS of familial IgAN have reported linkages at 2q36, 4q26-31, 6q22-23 and 17q12-22, but no disease genes were identified within these areas. [7][8][9] Three GWAS that allows hypothesis-free examination have been performed for IgAN, leading to the identification of susceptibility alleles in the major histocompatibility complex (MHC) region on chromosome 6p [10][11][12] and additional loci on chromosomes 1q32, 22q12, 17p13 and 8p23. So far, no genetic variants or genes underlying these loci have been identified as causative or affecting the pathology, plausibly because of the presence of genetic/environmental and locus heterogeneity and to contribution from noncoding susceptibility alleles such as point mutations or structural genomic variants within intronic or promoter regions.…”

A SPRY2 mutation leading to MAPK/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy

“…Association studies identified distinct loci on chromosomes 6p21, 8p23, 17p13, 22q12, 1q32. 6,7 On the other hand, classical linkage studies performed on AD families identified additional loci on chromosomes 2q36, 4q26-31, 6q22, 17q12-22, [8][9][10] lending further support to the complex etiology and broad genetic heterogeneity of the disease.…”