Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis

Abstract

Background: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG.

Methods: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk.

Results: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in T_H2 cells and MG risk.

Conclusions: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

Keywords: Actionable druggable genome; Cell-type specificity; Genetic colocalization; Mendelian randomization; Myasthenia gravis.

Fig. 1

Flow diagram of study design. Using a variety of data sources, this study examined the instruments proposed for actionable druggable proteins, specifically cis-pQTL and cis-eQTL, against MG GWAS summary statistics. Subsequently, further investigation was conducted on the MR associations that exhibited statistical significance and provided evidence for colocalization, aiming to identify immune-cell-specific effects

Fig. 2

Miami plot with circles representing the MR results for gene/protein on MG. FDR, P value (FDR adjust); Black dashed line indicates the threshold for significance (FDR < 0.05) threshold. The x axis is the chromosome and gene start position of each MR finding in the cis region. The y axis represents the − log₁₀ FDR of the MR findings. MR findings with positive effects (increased level of gene expression/protein associated with increasing the MG risk) are represented by filled circles on the top half of the plot; Conversely, MR findings suggesting a negative effect, implying a reduced level of gene expression or protein linked to an elevated risk of MG, are illustrated in the lower half of the plot

Fig. 3

Forest plot showing MR estimate for genetically proxied gene and protein expression on MG and its subgroups. Forest plot showing MR estimate (95% CI) from two sample MR analyses. P are unadjusted. CI confidence interval. MR estimates of significant MR results used cis-eQTL instruments on MG and its subgroups. MR estimates of significant MR results used cis-pQTL instruments on MG and its subgroups

Fig. 4

LocusCompare plot depicting colocalization of the top SNP associated with eQTL surrounding CDC42BPB (A), PRSS36 (B) and CD226 (C) and MG GWAS. The top right plots show the association results in the MG GWAS; the bottom right plots represent the corresponding eQTL results; the left plot shows the colocalization of genetic association and eQTL signals. The SNP indicated by the purple diamond is the SNP for which the European LD information is shown

Fig. 5

LocusCompare plot depicting colocalization of the top SNP associated with pQTL surrounding CPN2 (A), CTSH (B) and PRSS8 (C)and MG GWAS. The top right plots show the association results in the MG GWAS; the bottom right plots represent the corresponding pQTL results; the left plot shows the colocalization of genetic association and eQTL signals. The SNP indicated by the purple diamond is the SNP for which the European LD information is shown

Fig. 6

Colocalization results between GWAS and eQTLs across immune cell types. PPH4 of shared genetic signal between GWAS and eQTLs for MG across different immune cell types