Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes.
Qin MaHengameh ShamsAlessandro DidonnaSergio E BaranziniBruce A C CreeStephen L HauserRoland G HenryJorge R OksenbergPublished in: Communications biology (2023)
Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this notable progress, understanding the biological context of these associations remains challenging, due in part to the complexity of linking GWAS results to causative genes and cell types. Here, we aimed to address this gap by integrating GWAS data with single-cell and bulk chromatin accessibility data and histone modification profiles from immune and nervous systems. MS-GWAS associations are significantly enriched in regulatory regions of microglia and peripheral immune cell subtypes, especially B cells and monocytes. Cell-specific polygenic risk scores were developed to examine the cumulative impact of the susceptibility genes on MS risk and clinical phenotypes, showing significant associations with risk and brain white matter volume. The findings reveal enrichment of GWAS signals in B cell and monocyte/microglial cell-types, consistent with the known pathology and presumed targets of effective MS therapeutics.
Keyphrases
- multiple sclerosis
- single cell
- white matter
- genome wide
- mass spectrometry
- cell therapy
- rna seq
- dna methylation
- ms ms
- gene expression
- stem cells
- high throughput
- copy number
- small molecule
- inflammatory response
- oxidative stress
- endothelial cells
- deep learning
- dna damage
- big data
- mesenchymal stem cells
- machine learning
- lipopolysaccharide induced
- spinal cord injury
- subarachnoid hemorrhage