AUTHOR=Ouyang Fu , Yuan Ping , Ju Yaxin , Chen Wei , Peng Zijun , Xu Hongbei 

TITLE=Alzheimer’s disease as a causal risk factor for diabetic retinopathy: a Mendelian randomization study

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1340608

DOI=10.3389/fendo.2024.1340608

ISSN=1664-2392

ABSTRACT=<sec><title>Objectives</title><p>This study aims to investigate the causal relationship between Alzheimer’s Disease (AD) and Diabetic Retinopathy (DR).</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>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 (<italic>P<sub>FDR</sub></italic>)=0.0201; GSMR: b<sub>xy</sub>=0.8936, b<sub>xy_se</sub>=0.3759, <italic>P</italic>=0.0174), NPDR (OR: 2.7455; 95% CI: 1.3178-5.7197, <italic>P<sub>FDR</sub></italic>=0.0166; GSMR: b<sub>xy</sub>=0.9682, b<sub>xy_se</sub>=0.3802, <italic>P</italic>=0.0126), and PDR (OR: 2.3098; 95% CI: 1.2411-4.2986, <italic>P<sub>FDR</sub></italic>=0.0164; GSMR: b<sub>xy</sub>=0.7962, b<sub>xy_se</sub>=0.3205, <italic>P</italic>=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.</p></sec><sec><title>Discussion</title><p>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.</p></sec>