Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration

ABSTRACT Background Age-related macular degeneration (AMD) is a leading cause of blindness in the industrialised world and is projected to affect >280 million people worldwide by 2040. Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study. Methods We evaluated the effect of 4,591 exposure traits on early AMD using univariable MR. Statistically significant results were explored further using: validation in an advanced AMD cohort; MR Bayesian model averaging (MR-BMA); and multivariable MR. Results Overall, 44 traits were found to be putatively causal for early AMD in univariable analysis. Serum proteins that were found to have significant relationships with AMD included S100-A5 (odds ratio [OR]=1.07, p-value=6.80E-06), cathepsin F (OR=1.10, p-value=7.16E-05) and serine palmitoyltransferase 2 (OR=0.86, p-value=1.00E-03). Univariable MR analysis also supported roles for complement and immune cell traits. Although numerous lipid traits were found to be significantly related to AMD, MR-BMA suggested a driving causal role for serum sphingomyelin (marginal inclusion probability [MIP]=0.76; model-averaged causal effect [MACE]=0.29). Conclusions The results of this MR study support several putative causal factors for AMD and highlight avenues for future translational research. Funding This project was funded by the Wellcome Trust (224643/Z/21/Z); the University of Manchester’s Wellcome Institutional Strategic Support Fund (Wellcome ISSF) grant (204796/Z/16/Z); the UK National Institute for Health Research (NIHR) Academic Clinical Fellow and Clinical Lecturer Programmes; Retina UK and Fight for Sight (GR586); the Australian National Health and Medical Research Council (NHMRC) (1150144). IMPACT STATEMENT A phenome-wide Mendelian randomisation analysis revealed a causal link between age-related macular degeneration and a number of lipid, complement, immune cell, and serum protein traits, highlighting potential treatment targets.