Identification of new susceptibility loci for IgA nephropathy in Han Chinese

Abstract

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.

Figure 1. Recombination plots of the novel loci reaching genome-wide significance.

(a) rs7190997 at 16p11.2, (b) rs7634389 at 3q27.3, (c) rs2074038 at 11p11.2 and (d) rs2033562 at 8q22.3, showing P values obtained in the GWAS discovery (logistic regression) and in the combined analysis of GWAS and validation 1, 2 and 3 samples (fixed-effects meta-analysis).

Figure 2. Recombination plots of the three independent loci at the defensin locus, showing P values obtained in the GWAS discovery (logistic regression) and in the combined analysis of GWAS and validation 1, 2 and 3 samples (fixed-effects meta-analysis).

The two novel signals are in low linkage disequilibrium with rs2738058, which tags the previously reported SNP rs2738048 and are separated from these SNPs by regions of high recombination rates.