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

• DOI: 10.7554/elife.88768.3
• Publication Date: 2024-12-17T17:40:50Z
• Authors: Thomas P Spargo; Lachlan Gilchrist; Guy P Hunt; Richard JB Dobson; Petroula Proitsi; Ammar Al-Chalabi; Oliver Pain; Alfredo Iacoangeli
• Keywords: 0303 health sciences; QH301-705.5; Science; Q; R; Genetics and Genomics; 3. Good health; local genetic correlation; 03 medical and health sciences; fine-mapping; Medicine; neurodegenerative diseases; colocalisation; Biology (General)

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.