Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy
Authors: Li Ming , Wang Ling , Shi Dian-Chun , Foo Jia-Nee , Zhong Zhong , Khor Chiea-Chuen , Lanzani Chiara , Citterio Lorena , Salvi Erika , Yin Pei-Ran , Bei Jin-Xin , Wang Li , Liao Yun-Hua , Chen Jian , Chen Qin-Kai , Xu Gang , Jiang Geng-Ru , Wan Jian-Xin , Chen Meng-Hua , Chen Nan , Zhang Hong , Zeng Yi-Xin , Liu Zhi-Hong , Liu Jian-Jun , Yu Xue-Qing 
Published: September 2020

Significance Statement
Eighteen genetic risk loci for IgA nephropathy (IgAN) have been identified by genome-wide association studies (GWAS), but they only explain a small proportion of overall risk. By performing a three-stage meta-GWAS analysis in 10,546 patients and 21,871 healthy controls, the authors discovered three novel genetic risk loci on 1p36.13 (rs2240335), 1q23.1 (rs6427389), and 6p25.3 (rs6942325), implicating the roles of FCRL3, DUSP22.IRF4, and PADI4 in IgAN development. Through HLA imputation analyses, we revealed multiple independent associations within the MHC region. Besides the DEFA locus, they also discovered the genetic heterogeneity of six additional loci between Chinese and European populations. These findings have advanced the biologic understanding of IgAN and provided novel insight into the ethnic differences of genetic susceptibility.

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.