Exome Chip Analyses And Genetic Risk For Iga Nephropathy Among Han Chinese

Background and objectives IgAnephropathy is themost commonformofprimaryGNworldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgAnephropathy. Evidence for genetic factors in IgAnephropathy comes also fromgenome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. Design, setting, participants, & measurementsWe performed a two-stage exome chip-based association study in 13,242 samples, including 3363 patientswith IgAnephropathy and9879 healthy controls ofHanChinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored. Results We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (Pmeta, 531025) in single-variant associations. These novel non-HLA variantswere annotated as expression-associated single-nucleotide polymorphisms andwere located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene- based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy. Conclusions Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.