Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
Johnathan Cooper-Knock
Department of Neuroscience, Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, United Kingdom
Stuart MacGregor
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
Hui Guo
Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
Tariq Aslam
Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, School of Health Sciences, University of Manchester, Manchester, United Kingdom
Eleanor Sanderson
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom
Graeme CM Black
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Manchester Centre for Genomic Medicine, Saint Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom
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 4591 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 estimate [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; 200990/Z/16/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).
