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bioRxiv · 10.1101/2021.01.15.426824

Association of a common genetic variant with Parkinson's disease is propagated through microglia

Langston, R.·Beilina, A.·Reed, X.·Singleton, A.·Blauwendraat, C.·Gibbs, J. R.·Cookson, M. R.
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Abstract

Studies of the genetic basis of Parkinsons disease (PD) have identified many disease-associated genetic variants, but the mechanisms linking variants to pathogenicity are largely unknown. PD risk is attributed to both coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene and to common non-coding variation upstream of the LRRK2 locus. Here we show that the influence of genotype at non-coding variant rs76904798 on LRRK2 expression is propagated specifically through microglia, in contrast to evaluations based on general rather than genotype-dependent expression. We find evidence of microglia-specific regulatory regions that may modulate LRRK2 expression using single nuclei sequencing analyses of human frontal cortex and confirm these results in a human induced pluripotent stem cell-derived microglia model. Our study demonstrates that cell type is an important consideration in interrogation of the role of non-coding variation in disease pathogenesis.

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Langston, R., Beilina, A., Reed, X., Singleton, A., Blauwendraat, C., Gibbs, J. R., Cookson, M. R.. 2021-01-17. Association of a common genetic variant with Parkinson's disease is propagated through microglia. https://doi.org/10.1101/2021.01.15.426824

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