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

Abstract

Objectives: We 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.

Methods: We 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).

Results: There 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.

Interpretation: For AD and PD, we found significant enrichment of heritability in annotations marking gene activity in immune cells.

Figure 1

Enrichment of cell‐type groups as used in Finucane et al.31 The black dashed lines at −log₁₀(P) = 2.9 are the cutoff for Bonferroni significance.

Figure 2

Enrichment of immune cell annotations. The black dashed lines at −log₁₀(P) = 3.6 are the cutoff for Bonferroni significance. White bars = tissue; purple bars = CD34 (marker of immature hematopoietic cells – not strictly adaptive or innate); light blue bars = marker of T cells; dark blue bar = marker of B cells; royal blue bars = cells of the adaptive immune system; pink bars = cells of the innate immune system.