Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy

Abstract

Background: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.

Methods: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.

Results: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10^-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10^-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10^-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).

Conclusions: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.

Keywords: IgA nephropathy; common variants; genome-wide association study; meta-analysis.

Graphical abstract

Figure 1.

The three novel loci (red) and known loci (black) in the Manhattan plot of GWMA results at the discovery stage. Manhattan plot of the P values of association obtained by GWMA for IgAN based on 2628 patients and 11,563 controls. Plot obtained after dividing samples into three parts (Northern Chinese, Southern Chinese of our GWAS data^,, and Northern Chinese in Gharavi et al.’s GWAS data^,) in 3,611,808 SNPs. Negative log10-transformed P values for each SNP (y axis) are plotted by chromosomal position (x axis). The red and green lines represent the thresholds for genome-wide, statistically significant associations (P=5×10⁻⁸) and suggestive associations (P=1×10⁻⁵), respectively. A total of 11 known loci defined as loci that were previously published with genome-wide significance (P<5×10⁻⁸) were labeled black. Significant loci identified in the discovery stage of our study at genome-wide significance (P<5×10⁻⁸) were labeled red.

Figure 2.

Three novel genetic risk loci reaching genome-wide significance. (A) rs6427389 at 1q23.1 (FCRL3); (B) rs6942325 at 6p25.3 (DUSP22, IRF4); and (C) rs2240335 at 1p36.13 (PADI4). Shown are P values obtained in GWAS discovery, in the combined analysis of GWAS and Chinese validation samples, and/or in silico European samples (fixed-effects meta-analysis). Chr1, chromosome 1; chr6, chromosome 6; val, validation.

Figure 3.

The forest plots of three novel loci across the three discovery and two validation samples. (A) rs6427389 at 1q23.1 (FCRL3); (B) rs6942325 at 6p25.3 (DUSP22, IRF4); and (C) rs2240335 at 1p36.13 (PADI4). Shown are the associations in the discovery stage (across Northern Chinese samples, Southern Chinese samples, and the Chinese samples in Gharavi et al.’s study^,), and the validation stage (Northern Chinese, Southern Chinese, and Gharavi et al.’s Italian population [Europeans]). On the left, each study is indicated. The plots show the study-specific association estimates (ORs) and 95% confidence intervals for the discovery and validation stage studies, presented as bars. GWAS 1, Northern Chinese samples; GWAS 2, Southern Chinese samples; GWAS 3, Chinese samples in Gharavi et al.’s study; validation 1, Northern Chinese; validation 2, Southern Chinese; validation European, Gharavi et al.’s Italian population.