1. Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis
- Author
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Maren Stolp Andersen, Lynne Krohn, Ziv Gan-Or, Lasse Pihlstrøm, Inge R. Holtman, Sara Bandres-Ciga, Regina H. Reynolds, Mina Ryten, John Hardy, and Molecular Neuroscience and Ageing Research (MOLAR)
- Subjects
0301 basic medicine ,Multifactorial Inheritance ,Linkage disequilibrium ,Parkinson's disease ,Locus (genetics) ,Disease ,Biology ,Polymorphism, Single Nucleotide ,Risk Assessment ,Linkage Disequilibrium ,Monocytes ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Humans ,Genetic Predisposition to Disease ,Epigenetics ,Genetic association ,Genetics ,Immunity, Cellular ,Parkinson Disease ,medicine.disease ,Chromatin ,Receptors, Purinergic P2Y12 ,Clopidogrel ,030104 developmental biology ,Neurology ,Chromosomes, Human, Pair 3 ,Microglia ,Neurology (clinical) ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Objective Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types. Methods We used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus. Results We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3. Interpretation Our results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease. This article is protected by copyright. All rights reserved.
- Published
- 2021