Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy
Authors: Li Ming , Wang Yan-Na , Wang Ling , Meah Wee-Yang , Shi Dian-Chun , Heng Khai-Koon , Wang Li , Khor Chiea-Chuen , Bei Jin-Xin , Cheng Ching-Yu , Aung Tin , Liao Yun-Hua , Chen Qin-Kai , Gu Jie-Ruo , Kong Yao-Zhong , Lee Jimmy , Chong Siow-Ann , Subramaniam Mythily , Foo Jia-Nee , Cai Feng-Tao , Jiang Geng-Ru , Xu Gang , Wan Jian-Xin , Chen Meng-Hua , Yin Pei-Ran , Dong Xiu-Qing , Feng Shao-Zhen , Tang Xue-Qing , Zhong Zhong , Tan Eng-King , Chen Nan , Zhang Hong , Liu Zhi-Hong , Tai E. Shyong , Liu Jian-Jun , Yu Xue-Qing 
Published: October 2023

Significance Statement
Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Background
Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated.

Methods
We performed a three-stage exome chip–based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression.

Results
We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10−11). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10−11), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03).

Conclusions
Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.