Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics

Thomas P Spargo; Lachlan Gilchrist; Guy P Hunt; Richard J B Dobson; Petroula Proitsi; Ammar Al-Chalabi; Oliver Pain; Alfredo Iacoangeli

doi:10.7554/eLife.88768

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Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics

Journal article

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Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics

Thomas P Spargo, Lachlan Gilchrist, Guy P Hunt, Richard J B Dobson, Petroula Proitsi, Ammar Al-Chalabi, Oliver Pain and Alfredo Iacoangeli

eLife, Vol.12, pp.1-17

2024

DOI: https://doi.org/10.7554/eLife.88768

PMID: 39688956

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Abstract

Alzheimer Disease - genetics

Amyotrophic Lateral Sclerosis - genetics

Genetic Loci

Genetic Predisposition to Disease

Genome-Wide Association Study

Humans

Mental Disorders - genetics

Parkinson Disease - genetics

Schizophrenia - genetics

Continued methodological advances have enabled numerous statistical approaches for the analysis of summary statistics from genome-wide association studies. Genetic correlation analysis within specific regions enables a new strategy for identifying pleiotropy. Genomic regions with significant 'local' genetic correlations can be investigated further using state-of-the-art methodologies for statistical fine-mapping and variant colocalisation. We explored the utility of a genome-wide local genetic correlation analysis approach for identifying genetic overlaps between the candidate neuropsychiatric disorders, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson's disease, and schizophrenia. The correlation analysis identified several associations between traits, the majority of which were loci in the human leukocyte antigen region. Colocalisation analysis suggested that disease-implicated variants in these loci often differ between traits and, in one locus, indicated a shared causal variant between ALS and AD. Our study identified candidate loci that might play a role in multiple neuropsychiatric diseases and suggested the role of distinct mechanisms across diseases despite shared loci. The fine-mapping and colocalisation analysis protocol designed for this study has been implemented in a flexible analysis pipeline that produces HTML reports and is available at: https://github.com/ThomasPSpargo/COLOC-reporter.

Details

Title: Statistical examination of shared loci in neuropsychiatric diseases using genome-wide association study summary statistics
Authors/Creators: Thomas P Spargo - King's College London
Lachlan Gilchrist - King's College London
Guy P Hunt - Murdoch University
Richard J B Dobson - NIHR Biomedical Research Centre at University College London Hospitals NHS21 Foundation Trust, London, United Kingdom
Petroula Proitsi - Queen Mary University of London
Ammar Al-Chalabi - King's College Hospital
Oliver Pain - King's College London
Alfredo Iacoangeli - King's College London
Publication Details: eLife, Vol.12, pp.1-17
Publisher: eLife Sciences Publications Ltd.
Number of pages: 17
Grant note: MR/L501529/1 / Medical Research Council 772376-EScORIAL / Horizon 2020 MR/R024804/1 / Medical Research Council DRIVE-Health Centre for Doctoral Training / King's College London Wellcome Trust 10.35802/222811 / Wellcome Trust ES/L008238/1 / Economic and Social Research Council 259867 / European Community's Health Seventh Framework Programme 633413 / Horizon 2020
Identifiers: 991005732475407891
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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