Genetic Risk for Neurodegenerative Conditions is Linked to Disease-specific Microglial Pathways
Aydan Askarova, Reuben M. Yaa, Sarah J. Marzi, Alexi Nott.
Abstract
Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression.
Introduction
Genetics plays a significant role in the etiology of neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Familial forms have been identified for AD, PD and ALS that exhibit Mendelian patterns of inheritance and are associated with rare variants with strong effect sizes. While the genetics underlying familial cases have been informative in our understanding of disease etiology, most individuals presenting with neurogenerative disorders, including MS, have sporadic forms of the disease.
Materials and Methods:
PLAC-seq data for human microglia, neurons and oligodendrocytes was pre-processed by Nott et al., 2019. PLAC-seq data was generated using epilepsy resections of the frontal, parietal and temporal cortex of seven individuals aged 5 months to 17 years of Caucasian, Hispanic and Pacific Islander ethnicities (6 males/1 female). PLAC-seq chromatin interactions were anchored to active gene promoters by immunoprecipitation of histone H3 lysine 4 trimethylation (H3K4me3), which is a histone modification enriched at active gene promoters. Chromatin interactions were 5 kb resolution and were anchored to promoters using chromatin immunoprecipitation of the histone modification H3K4me3.
Discussion
Incorporation of enhancer-to-promoter interactomes for microglia, neurons and oligodendrocytes with GWAS summary statistics enabled us to identify the cell types and genes associated with the genetic risk of brain disorders. Partitioned heritability analysis highlighted microglia as an important cell type underlying genetic susceptibility across multiple neurodegenerative conditions. Accordingly, enhancer-to-promoter interactomes identified the greatest number of predicted risk genes in microglia for AD, PD, MS and ALS. Previous studies have shown both the importance of active regulatory regions and that AD GWAS-risk is associated with gene regulatory regions in microglia as well as monocytes and macrophages.
Acknowledgments
We thank Dr Hyejun Won for the discussions on H-MAGMA. We thank the Skene, Marzi, Johnson and Nott groups for advice and helpful discussion, in particular, Dr Alan Murphy, Dr Brian Schilder, Dr Kitty Murphy and Dr Alex Haglund.
Citation: Askarova A, Yaa RM, Marzi SJ, Nott A (2025) Genetic risk for neurodegenerative conditions is linked to disease-specific microglial pathways. PLoS Genet 21(4): e1011407. https://doi.org/10.1371/journal.pgen.1011407
Editor: Annie Vogel Ciernia, The University of British Columbia, CANADA
Received: August 29, 2024; Accepted: March 24, 2025; Published: April 9, 2025.
Copyright: © 2025 Askarova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Code is available: https://github.com/aydanasg/cell_hmagma. PLAC-seq, H3K27ac ChIP-seq, H3K4me3 ChIP-seq and ATAC-seq datasets were taken from (1) and processed data is available: https://github.com/nottalexi/brain-cell-type-peak-files.
Funding: AN and SJM are supported by the UK Dementia Research Institute [award number UKDRI- 5208 to AN; UKDRI-6009 to SJM] through UK DRI Ltd, principally funded by the Medical Research Council. AN, SJM and RMY received salaries from the UK Dementia Research Institute. AN and SJM are supported by the Edmond and Lily Safra Early Career Fellowship Program. AN is supported by The Dunhill Medical Trust [grant number AISRPG2305\26]. AA received a stipend funded by the Imperial College London President’s PhD Scholarships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
