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Association of a common genetic variant with Parkinson's disease is mediated by microglia

Rebekah G Langston1,2, Alexandra Beilina1, Xylena Reed1,3

  • 1Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Science Translational Medicine
|July 27, 2022
PubMed

Insights

Parkinson's disease risk linked to genetic variations is specifically influenced by microglia, the brain's immune cells. This study reveals how noncoding variants in the LRRK2 gene impact gene expression in these specific cells.

Area of Science:

  • Neurogenetics
  • Cell Biology
  • Genomics

Background:

  • Genetic variants, including those in the LRRK2 gene, are associated with Parkinson's disease (PD) risk.
  • Mechanisms linking genome-wide association study (GWAS) variants to pathogenicity remain largely unknown.
  • Noncoding variations in the 5' region of the LRRK2 locus are implicated in PD risk.

Purpose of the Study:

  • To investigate the cell-type-specific mechanisms by which PD-associated noncoding variants influence LRRK2 expression.
  • To identify regulatory elements in microglia that modulate LRRK2 expression.
  • To elucidate the role of specific variants, like rs6581593, in LRRK2 regulation within microglia.

Main Methods:

  • Analysis of LRRK2 expression in various human brain cell types.
  • Identification of microglia-specific regulatory chromatin regions in human frontal cortex and substantia nigra.
  • Utilizing a human-induced pluripotent stem cell-derived microglia model.
  • Performing a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen.

Main Results:

  • The influence of PD-associated noncoding variation on LRRK2 expression is specific to microglia.
  • Microglia-specific regulatory chromatin regions modulating LRRK2 expression were identified in key brain areas.
  • A regulatory DNA element containing the single-nucleotide variant rs6581593 was shown to influence LRRK2 expression in microglia via CRISPRi screening.

Conclusions:

  • Cell type is a critical consideration when assessing the pathogenicity of noncoding genetic variation.
  • This study reveals a microglia-specific mechanism underlying the association between the 5' region of LRRK2 and Parkinson's disease risk.
  • Findings highlight the importance of microglia in neurodegenerative disease pathogenesis driven by genetic factors.

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