Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus

Abstract

Genome-wide association studies (GWAS) have identified many loci for systemic lupus erythematosus (SLE). However, identification of functionally relevant genes remains a challenge. The aim of this study was to highlight potential causal genes for SLE in the GWAS loci. By applying Mendelian randomization (MR) methods, such as summary data-based MR (SMR), generalized SMR and MR pleiotropy residual sum and outlier, we identified DNA methylations in 15 loci and mRNA expression of 21 genes that were causally associated with SLE. The identified genes enriched in 14 specific KEGG pathways (e.g. SLE, viral carcinogenesis) and two GO terms (interferon-c-mediated signaling pathway and innate immune response). Among the identified genes, UBE2L3 and BLK variants were significantly associated with UBE2L3 and BLK methylations and gene expressions, respectively. UBE2L3 was up-regulated in SLE patients in several types of immune cells. Methylations (e.g. cg06850285) and mRNA expression of UBE2L3 were causally associated with SLE. Methylation site cg09528494 and mRNA expression of BLK were causally associated with SLE. BLK single nucleotide polymorphisms that were significantly associated with SLE were strongly associated with plasma cathepsin B level. Deep analysis identified that plasma cathepsin B level was causally associated with SLE. In summary, this study identified hundreds of DNA methylations and genes as potential risk factors for SLE. Genetic variants in UBE2L3 gene might affect SLE by influencing gene expression. Genetic variants in BLK gene might affect SLE by influencing BLK gene expression and plasma cathepsin B protein level.

Single cell sequencing analysis identifies genetics-modulated ORMDL3+ cholangiocytes having higher metabolic effects on primary biliary cholangitis

“…Moreover, ORMDL3 has also been extensively reported to be linked with other inflammatory diseases, including childhood asthma [ 45 ], inflammatory bowel diseases [ 38 ], rheumatoid arthritis [ 39 ], and Crohn’s disease [ 46 ]. Functional enrichment analyses uncovered that these genetics-risk genes were notably enriched in several biological processes or disease-terms, which are relevant to autoimmune phenotypes [ 47 , 48 ]. Together, these identified genes are more likely to be genuine genes implicated in PBC risk.…”

Combination of single cell sequencing data and GWAS summary statistics reveals genetically-influenced liver cell types for primary biliary cholangitis

“…Moreover, ORMDL3 has also been extensively reported to be linked with other inflammatory diseases, including childhood asthma 62 , inflammatory bowel diseases 53 , rheumatoid arthritis 54 , and Crohn’s disease 63 . Functional enrichment analyses uncovered that these risk genes were notably enriched in several biological processes or disease-terms that are relevant to autoimmune phenotypes 64,65 . Together, these results suggest these identified genes are more likely to be genuine genes implicated in PBC risk.…”

A catalog of GWAS fine-mapping efforts in autoimmune disease

“…After a GWAS, many genome-wide studies have assayed intermediate molecular traits including epigenetic marks, gene expression levels, and chromatin interaction datasets. 3 , 30 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 An array of computational approaches have been developed to test the impact of genetic variation on these intermediate traits and to help researchers infer causal relationships between the molecular phenotypes and the downstream disease risk. Gene-based association tests of rare variants have been used to increase the statistical power and to enable direct identification of trait-relevant genes.…”