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

doi:10.7554/eLife.82546

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 journal › Article › peer-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 language	English
Article number	e82546
Journal	eLife
Volume	12
DOIs	https://doi.org/10.7554/eLife.82546
Publication status	Published - 27 Jan 2023

Keywords

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

Access to Document

10.7554/eLife.82546Licence: CC BY

Cite this

@article{af8392a11e69485a8761d2d49d12103f,

title = "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 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).",

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

author = "Julian, {Thomas H} and Johnathan Cooper-Knock and Stuart MacGregor and Hui Guo and Tariq Aslam and Eleanor Sanderson and Black, {Graeme C M} and Sergouniotis, {Panagiotis I}",

note = "{\textcopyright} 2023, Julian et al.",

year = "2023",

month = jan,

day = "27",

doi = "10.7554/eLife.82546",

language = "English",

volume = "12",

journal = "eLife",

issn = "2050-084X",

publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration

AU - Julian, Thomas H

AU - Cooper-Knock, Johnathan

AU - MacGregor, Stuart

AU - Guo, Hui

AU - Aslam, Tariq

AU - Sanderson, Eleanor

AU - Black, Graeme C M

AU - Sergouniotis, Panagiotis I

PY - 2023/1/27

Y1 - 2023/1/27

N2 - 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).

AB - 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).

KW - Humans

KW - Risk Factors

KW - Bayes Theorem

KW - Australia

KW - Macular Degeneration/genetics

KW - Causality

KW - Genome-Wide Association Study

KW - Polymorphism, Single Nucleotide

U2 - 10.7554/eLife.82546

DO - 10.7554/eLife.82546

M3 - Article

C2 - 36705323

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e82546

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this