Exploring genes for immunoglobulin A nephropathy: a summary data-based mendelian randomization and FUMA analysis

Abstract

Background: Immunoglobulin A nephropathy (IgAN) is a complex autoimmune disease, and the exact pathogenesis remains to be elucidated. This study aimed to explore genes underlying the pathogenesis of IgAN.

Methods: We conducted the summary data-based Mendelian randomization (SMR) analysis and performed functional mapping and annotation using FUMA to explore genetic loci that are potentially involved in the pathogenies of IgAN. Both analyses used summarized data of a recent genome-wide association study (GWAS) on IgANs, which included 477,784 Europeans (15,587 cases and 462,197 controls) and 175,359 East Asians (71 cases and 175,288 controls). We performed SMR analysis using Consortium for the Architecture of Gene Expression (CAGE) expression quantitative trait loci (eQTL) data and replicated the analysis using Genotype-Tissue Expression (GTEx) eQTL data.

Results: Using the CAGE eQTL data, our SMR analysis identified 32 probes tagging 25 unique genes whose expression were pleiotropically associated with IgAN, with the top three probes being ILMN_2150787 (tagging HLA-C, P_SMR= 2.10 × 10^-18), ILMN_1682717 (tagging IER3, P_SMR= 1.07 × 10^-16) and ILMN_1661439 (tagging FLOT1, P_SMR=1.16 × 10^-14). Using GTEx eQTL data, our SMR analysis identified 24 probes tagging 24 unique genes whose expressions were pleiotropically associated with IgAN, with the top three probes being ENSG00000271581.1 (tagging XXbac-BPG248L24.12, P_SMR= 1.44 × 10^-10), ENSG00000186470.9 (tagging BTN3A2, P_SMR= 2.28 × 10^-10), and ENSG00000224389.4 (tagging C4B, P_SMR= 1.23 × 10 ^-9). FUMA analysis identified 3 independent, significant and lead SNPs, 2 genomic risk loci and 39 genes that are potentially involved in the pathogenesis of IgAN.

Conclusion: We identified many genetic variants/loci that are potentially involved in the pathogenesis of IgAN. More studies are needed to elucidate the exact mechanisms of the identified genetic variants/loci in the etiology of IgAN.

Keywords: Expression quantitative trait loci; Functional mapping; Genome-wide association study; Immunoglobulin A nephropathy; Summary data-based Mendelian randomization.