Single cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease

Lin, Z.; Parker, J.; Nithianandam, V.; Mathivanan, S.; Wang, T.; Liao, Z.; Simmons, S. K.; Tuncali, I.; Adiconis, X.; Haywood, N.; Weykopf, B.; Teng, X.; Sharma, M.; Yuan, J.; Baecher-Allan, C.; Dong, X.; Beach, T. G.; Serrano, G. E.; Levin, J. Z.; Zhang, S.; Feany, M. B.; Scherzer, C. R.

doi:10.64898/2026.04.24.720642

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bioRxiv · 10.64898/2026.04.24.720642

Single cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease

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Abstract

Synucleinopathies affect [~]15 million people and are classically divided into neuronal (Parkinsons disease (PD), dementia with Lewy bodies) and glial (multiple system atrophy) disorders. Here we challenge this dichotomy. We functionally fine-map 90 PD GWAS signals across nine cell types in cortex and substantia nigra using disease-context, population-scale single-nucleus eQTL meta-analysis (N = 1,197), bulk brain eQTL analysis (N = 1,182), and Mendelian randomization. A stringent causal framework integrates single-nucleus allelic imbalance (snASE) with orthogonal validation. We identify 125 functional risk genes for 50 loci--nearly doubling supported genes--and assign genes and cell types to over half of GWAS signals. Unexpectedly, 51% of risk genes are regulated in glia, particularly oligodendrocytes and their precursors. Across cell types, risk converges on a shared glial-neuronal vesiculopathy network. These findings uncover a convergent glial-neuronal risk architecture and establish a single-cell atlas for context-aware gene discovery and precision therapeutics for PD.

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Lin, Z., Parker, J., Nithianandam, V., Mathivanan, S., Wang, T., Liao, Z., Simmons, S. K., Tuncali, I., Adiconis, X., Haywood, N., Weykopf, B., Teng, X., Sharma, M., Yuan, J., Baecher-Allan, C., Dong, X., Beach, T. G., Serrano, G. E., Levin, J. Z., Zhang, S., Feany, M. B., Scherzer, C. R.. 2026-04-24. Single cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease. https://doi.org/10.64898/2026.04.24.720642

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