Alzheimer's disease as a causal risk factor for diabetic retinopathy: a Mendelian randomization study.

ABSTRACT

Objectives: This study aims to investigate the causal relationship between Alzheimer's Disease (AD) and Diabetic Retinopathy (DR). Methods: Employing Mendelian Randomization (MR), Generalized Summary-data-based Mendelian Randomization (GSMR), and the MR-Steiger test, this study scrutinizes the genetic underpinnings of the hypothesized causal association between AD and DR, as well as its Proliferative DR (PDR) and Non-Proliferative DR (NPDR) subtypes. Comprehensive data from Genome-Wide Association Studies (GWAS) were analyzed, specifically AD data from the Psychiatric Genomics Consortium (71,880 cases/383,378 controls), and DR, PDR, and NPDR data from both the FinnGen consortium (FinnGen release R8, DR 5,988 cases/314,042 controls; PDR 8,383 cases/329,756 controls; NPDR 3,446 cases/314,042 controls) and the IEU OpenGWAS (DR 14,584 cases/176,010 controls; PDR 8,681 cases/204,208 controls; NPDR 2,026 cases/204,208 controls). The study also incorporated Functional Mapping and Annotation (FUMA) for an in-depth analysis of the GWAS results. Results: The MR analyses revealed that genetic susceptibility to AD significantly increases the risk of DR, as evidenced by GWAS data from the FinnGen consortium (OR 2.5090; 95% confidence interval (CI)1.2102-5.2018, false discovery rate P-value (PFDR)=0.0201; GSMR bxy=0.8936, bxy_se=0.3759, P=0.0174), NPDR (OR 2.7455; 95% CI 1.3178-5.7197, PFDR=0.0166; GSMR bxy=0.9682, bxy_se=0.3802, P=0.0126), and PDR (OR 2.3098; 95% CI 1.2411-4.2986, PFDR=0.0164; GSMR bxy=0.7962, bxy_se=0.3205, P=0.0129) using DR GWAS from FinnGen consortium. These results were corroborated by DR GWAS datasets from IEU OpenGWAS. The MR-Steiger test confirmed a significant association of all identified instrumental variables (IVs) with AD. While a potential causal effect of DR and its subtypes on AD was identified, the robustness of these results was constrained by a low power value. FUMA analysis identified OARD1, NFYA, TREM1 as shared risk genes between DR and AD, suggesting a potential genetic overlap between these complex diseases. Discussion: This study underscores the contribution of AD to an increased risk of DR, as well as NPDR and PDR subtypes, underscoring the necessity of a holistic approach in the management of patients affected by these conditions.