Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity

Clare E. West; Mohd Karim; Maria J. Falaguera; Leo Speidel; Charlotte J. Green; Lisa Logie; Jeremy Schwartzentruber; David Ochoa; Janet M. Lord; Michael A. J. Ferguson; Chas Bountra; Graeme F. Wilkinson; Beverley Vaughan; Andrew R. Leach; Ian Dunham; Brian D. Marsden

doi:10.1038/s41597-023-02513-4

Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity

Clare E. West (Lead / Corresponding author), Mohd Karim, Maria J. Falaguera, Leo Speidel, Charlotte J. Green, Lisa Logie, Jeremy Schwartzentruber, David Ochoa, Janet M. Lord, Michael A. J. Ferguson, Chas Bountra, Graeme F. Wilkinson, Beverley Vaughan, Andrew R. Leach, Ian Dunham, Brian D. Marsden

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Abstract

Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

Original language	English
Article number	655
Number of pages	13
Journal	Scientific Data
Volume	10
DOIs	https://doi.org/10.1038/s41597-023-02513-4
Publication status	Published - 25 Sept 2023

Keywords

Computational biology and bioinformatics
Diseases
Genomics
Target identification

ASJC Scopus subject areas

Statistics and Probability
Information Systems
Education
Computer Science Applications
Statistics, Probability and Uncertainty
Library and Information Sciences

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10.1038/s41597-023-02513-4Licence: CC BY

Final published versionFinal published version, 1.55 MBLicence: CC BY

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West, C. E., Karim, M., Falaguera, M. J., Speidel, L., Green, C. J., Logie, L., Schwartzentruber, J., Ochoa, D., Lord, J. M., Ferguson, M. A. J., Bountra, C., Wilkinson, G. F., Vaughan, B., Leach, A. R., Dunham, I., & Marsden, B. D. (2023). Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity. Scientific Data, 10, Article 655. https://doi.org/10.1038/s41597-023-02513-4

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title = "Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity",

abstract = "Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.",

keywords = "Computational biology and bioinformatics, Diseases, Genomics, Target identification",

author = "West, {Clare E.} and Mohd Karim and Falaguera, {Maria J.} and Leo Speidel and Green, {Charlotte J.} and Lisa Logie and Jeremy Schwartzentruber and David Ochoa and Lord, {Janet M.} and Ferguson, {Michael A. J.} and Chas Bountra and Wilkinson, {Graeme F.} and Beverley Vaughan and Leach, {Andrew R.} and Ian Dunham and Marsden, {Brian D.}",

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doi = "10.1038/s41597-023-02513-4",

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West, CE, Karim, M, Falaguera, MJ, Speidel, L, Green, CJ, Logie, L, Schwartzentruber, J, Ochoa, D, Lord, JM, Ferguson, MAJ, Bountra, C, Wilkinson, GF, Vaughan, B, Leach, AR, Dunham, I & Marsden, BD 2023, 'Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity', Scientific Data, vol. 10, 655. https://doi.org/10.1038/s41597-023-02513-4

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AU - West, Clare E.

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AU - Falaguera, Maria J.

AU - Speidel, Leo

AU - Green, Charlotte J.

AU - Logie, Lisa

AU - Schwartzentruber, Jeremy

AU - Ochoa, David

AU - Lord, Janet M.

AU - Ferguson, Michael A. J.

AU - Bountra, Chas

AU - Wilkinson, Graeme F.

AU - Vaughan, Beverley

AU - Leach, Andrew R.

AU - Dunham, Ian

AU - Marsden, Brian D.

PY - 2023/9/25

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N2 - Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

AB - Advancing age is the greatest risk factor for developing multiple age-related diseases. Therapeutic approaches targeting the underlying pathways of ageing, rather than individual diseases, may be an effective way to treat and prevent age-related morbidity while reducing the burden of polypharmacy. We harness the Open Targets Genetics Portal to perform a systematic analysis of nearly 1,400 genome-wide association studies (GWAS) mapped to 34 age-related diseases and traits, identifying genetic signals that are shared between two or more of these traits. Using locus-to-gene (L2G) mapping, we identify 995 targets with shared genetic links to age-related diseases and traits, which are enriched in mechanisms of ageing and include known ageing and longevity-related genes. Of these 995 genes, 128 are the target of an approved or investigational drug, 526 have experimental evidence of binding pockets or are predicted to be tractable, and 341 have no existing tractability evidence, representing underexplored genes which may reveal novel biological insights and therapeutic opportunities. We present these candidate targets for exploration and prioritisation in a web application.

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Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity

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