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Aiming to identify causal factors and potential therapeutic targets for this common condition, we designed and undertook a phenome-wide Mendelian randomisation (MR) study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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\u221206), cathepsin F (OR = 1.10, p-value = 7.16E\u221205), and serine palmitoyltransferase 2 (OR = 0.86, p-value = 1.00E\u221203). 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The results of this MR study support several putative causal factors for AMD and highlight avenues for future translational research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>This project was funded by the Wellcome Trust (224643\/Z\/21\/Z; 200990\/Z\/16\/Z); the University of Manchester\u2019s 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).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.82546","type":"journal-article","created":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T05:15:14Z","timestamp":1673327714000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.82546","source":"Crossref","is-referenced-by-count":46,"title":["Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5488-5620","authenticated-orcid":true,"given":"Thomas H","family":"Julian","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027m9bs27","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of 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