Integration of multi-omics transcriptome-wide analysis for the identification of novel therapeutic drug targets in diabetic retinopathy

Abstract

Background: Diabetic retinopathy (DR) is the most important complication of Type 2 Diabetes (T2D) in eyes. Despite its prevalence, the early detection and management of DR continue to pose considerable challenges. Our research aims to elucidate potent drug targets that could facilitate the identification of DR and propel advancements in its therapeutic strategies.

Methods: A broad multi-omics exploration of DR was presented to decipher the drug targets of DR and proliferative diabetic retinopathy (PDR). Transcriptome-Wide Association Studies (TWAS), fine-mapping and conditional analysis were applied to unearth potential tissue-specific gene associations with DR. Summary Data-based Mendelian Randomization (SMR) provided secondary analysis of high confidence genes. Cis-instrument of druggable genes were extracted from the eQTLGen Consortium and PsychENCODE, facilitating drug-target MR supported by colocalization analysis. Phenome-Wide Association Studies (PheWAS) was conducted on the high confidence genes. Metabolomic and immunomic MR-profiling further augmented our research as complement.

Results: TWAS identified multiple robust genetic loci in both DR and PDR (WFS1, RPS26, and SRPK1) through genetic associations across different tissues. Meanwhile, we have delineated both the commonalities and discrepancies between DR and PDR at the transcriptomic level, represented by DCLRE1B as the hub gene that DR progressed into PDR. SMR revealed 92 key DR-related genes and 55 PDR-related genes. HLA-DQ family genes have a frequent occurrence, while RPS26, WFS1 and SRPK1 were validated as the genetic network's linchpins. Drug-target MR casted ERBB3 and SRPK1 as candidate effector genes for DR and PDR susceptibility. In addition, metabolomics and immunomics analyses also revealed multifaceted pathogenic factors for DR.

Conclusions: Our research offers targeted therapeutic insights for early-stage DR and facilitates multi-omic comparisons of it and PDR.

Keywords: Diabetic retinopathy (DR); Drug-target MR; Immunomics; Mendelian randomization (MR); Metabolomics; Multi-omics; Summary data-based Mendelian randomisation (SMR); Transcriptome-wide association studies (TWAS).