Exome Chip Analyses and Genetic Risk for IgA Nephropathy among Han Chinese
Shu‐Feng Zhou, Lam C. Tsoi, Yong Hu, Matthew T. Patrick, Kevin He, Céline C. Berthier, Yanming Li, Yan‐na Wang, Yuanyuan Qi, Yuemiao Zhang, Ting Gan, Yang Li, Ping Hou, Lijun Liu, Sufang Shi, Jicheng Lv, Huji Xu, Hong Zhang
Abstract
Background and objectives IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. Design, setting, participants, & measurements We performed a two-stage exome chip–based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese 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 ( P meta <5×10 −5 ) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were 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.