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

Thomas H Julian, Johnathan Cooper-Knock, Stuart MacGregor, Hui Guo, Tariq Aslam, Eleanor Sanderson, Graeme C M Black, Panagiotis I Sergouniotis

Research output: Contribution to journalArticlepeer-review

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 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).

Original languageEnglish
Article numbere82546
JournaleLife
Volume12
DOIs
Publication statusPublished - 27 Jan 2023

Keywords

  • Humans
  • Risk Factors
  • Bayes Theorem
  • Australia
  • Macular Degeneration/genetics
  • Causality
  • Genome-Wide Association Study
  • Polymorphism, Single Nucleotide

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