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other·epidemiology, geriatrics, endocrinology, cardiology, research methods·PMC10520009

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

Scientific Data · 16 authors, 11 centres

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TL;DR

This computational study integrated 1,394 genome-wide association studies (GWAS) of age-related traits to identify 1,006 genetic clusters sharing common signals. The analysis produced a set of 995 candidate genes, with 935 being novel, many enriched in immune pathways, offering new potential targets for age-related multimorbidity therapies.

Full summary

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The study used a computational approach to systematically combine 1,394 GWAS of age-related traits. It employed genetic co-localisation and LD-expansion to identify 1,006 clusters where multiple traits share a common genetic signal. From these, a 'TargetAge' gene set of 995 candidate causal genes was created, with 29% annotated to Hallmarks of Ageing and enrichment in immune response pathways. The set shows significant overlap with curated ageing gene sets but contains 935 novel genes. The analysis highlights potential drug repurposing opportunities (13% of genes targeted by existing drugs) and novel targets, including genes linked to clusters connecting conditions like atrial fibrillation and bone density (e.g., THRB), or cardiovascular diseases (e.g., EDNRA). Limitations include potential bias toward European populations and that clusters may contain overlapping but distinct genetic signals. The work provides a resource for exploring shared biological mechanisms and therapeutic opportunities for age-related multimorbidity.

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other

SPECIALTY

epidemiology

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AI pipeline

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ORIGINAL PAPER

PMC10520009

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

Scientific Data

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ABSTRACT

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. Subject terms: Target identification, Computational biology and bioinformatics, Diseases, Genomics

CITATION EXPORT

Clare E West, Mohd Karim, Maria J Falaguera et al.. Integrative GWAS and co-localisation analysis suggests novel genes associated with age-related multimorbidity. Scientific Data. (2023). https://doi.org/10.1038/s41597-023-02513-4

AUTHORS

16 · 11 CENTRES

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

1Centre for Medicines Discovery, University of Oxford, Oxford, UK
2Open Targets, Wellcome Genome Campus, Hinxton, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
4Francis Crick Institute, London, UK
5Genetics Institute, University College London, London, UK
6Drug Discovery Unit, University of Dundee, Dundee, UK
7Medicines Discovery Catapult, 35 Mereside Alderley Park, Macclesfield, Cheshire UK
8Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
9MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
10NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK
11Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK