Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

Abstract

ObjectivesWe assessed the current genetic evidence for the involvement of various cell types and tissue types in the etiology of neurodegenerative diseases, especially in relation to the neuroinflammatory hypothesis of neurodegenerative diseases.MethodsWe obtained large‐scale genome‐wide association study (GWAS) summary statistics from Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). We used multiple sclerosis (MS), an autoimmune disease of the central nervous system, as a positive control. We applied stratified LD score regression to determine if functional marks for cell type and tissue activity, and gene‐set lists were enriched for genetic heritability. We compared our results to those from two gene‐set enrichment methods (Ingenuity Pathway Analysis and enrichr).ResultsThere were no significant heritability enrichments for annotations marking genes active within brain regions, but there were significant heritability enrichments for annotations marking genes active within cell types that form part of both the innate and adaptive immune systems. We found this for MS (as expected) and also for AD and PD. The strongest signals were from the adaptive immune system (e.g., T cells) for PD, and from both the adaptive (e.g., T cells) and innate (e.g., CD14: a marker for monocytes, and CD15: a marker for neutrophils) immune systems for AD. Annotations from the liver were also significant for AD. Pathway analysis provided complementary results.InterpretationFor AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson’s disease pathogenesis

“…Given that monocyte activation by lipopolysaccharide occurs through TLR4-MyD88 signalling these findings suggested that TLR4-mediated activation of microglia/astrocytes generated a cell state of key importance in the development of PD. This finding is consistent with previous reports highlighting the involvement of the immune system in sporadic PD [5, 17, 38, 51]. …”

A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

“…Regions contributing to PD heritability were significantly enriched for acetylation of histone H3 at lysine 27 ( P = 0.001; Supplementary Table 1), a mark of active regulatory regions. PD heritability was also enriched for histone marks in central nervous system, adrenal, and pancreatic cell types (Supplementary Table 2), in agreement with a previous study 13 .…”

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

“…With these results in mind, it is tempting to speculate that PD presents genetically as more of a systemic disorder, with a bias to brain pathology, as opposed to a primary brain disorder. In support of this view, PD-associated risk variants have been found associated with monocytes and the innate immune system 13,40,41 , in addition to lymphocytes, mesendoderm, liver-and fat-cells 42 . Recent work has also demonstrated a causal relationship between BMI and PD 43 , which together with the repurposing of exenatide (a glucagon-like peptide-1 receptor agonist currently licensed for the treatment of type 2 diabetes) for the potential treatment of PD 44 , highlights the need to look beyond the brain and selective neuronal vulnerability.…”