Identification of Parkinson’s disease-associated regulatory variants in human dopaminergic neurons reveals modulators of SCARB2 and BAG3 expression [* Cross-Reference *]

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Déborah Gérard; Jochen Ohnmacht; Borja Gomez Ramos; Marie Catillon; Jafar Sharif; Nina Baumgarten; Dennis Hecker; Aurélien Ginolhac; Zied Landoulsi; Elena Valceschini; Aleksandar Raković; Christine Klein; Patrick May; Haruhiko Koseki; Marcel H. Schulz; Thomas Sauter; Rejko Krüger; Lasse Sinkkonen, 2026, "Identification of Parkinson’s disease-associated regulatory variants in human dopaminergic neurons reveals modulators of SCARB2 and BAG3 expression [* Cross-Reference *]", https://lore.list.lu/citation?persistentId=perma:LIST.BD4ORK, LIST Open Repository, V1

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Description	Abstract A hallmark of Parkinson’s disease (PD) is the degeneration of midbrain dopaminergic neurons (mDANs). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with PD, but causal variants and mechanisms remain unknown. Many PD-associated SNPs reside in regulatory regions, where they may disrupt transcription factor binding sites (TFBS) and alter gene expression. To assess how non-coding PD SNPs affect gene regulation in mDANs, we identify variants predicted to alter TF binding and functionally validate their effects in a cell type-specific context. We integrate time-series transcriptome and chromatin accessibility data from iPSC-derived neurons with chromatin topology and genetic variants. We profile 3D chromatin conformation in neuronal progenitors (smNPCs) and mDANs using LowC, identifying changes in A/B compartments and topologically associated domains. PD SNPs are enriched near genes expressed in mDANs, and we predict 254 regulatory variants that create or disrupt TFBS. Using chromatin conformation data, we link variants to target genes. At the BAG3 and SCARB2 loci, reporter assays in mDANs show reduced transcription driven by PD-associated alleles. Knock-down of NR2C2, a putative SCARB2 regulator, increases SCARB2 expression in differentiating neurons. The PD-associated SCARB2 allele shows reduced chromatin accessibility in mDANs and is associated with decreased expression in brain eQTL data. Insertion of PD-associated BAG3 allele by prime editing reduces chromatin accessibility across cell types, consistent with altered binding of LIM-homeodomain transcription factors. Together, these results prioritize functional PD SNPs and show that variants at SCARB2 and BAG3 modulate gene expression in mDANs, providing mechanistic insight into PD. (2026-03-27) *This entry has been automatically imported via OpenAlex by LIST harvest scripts. Please refer to https://doi.org/10.64898/2026.03.26.714241 for the original and latest version of the publication* (2026-07-01)
Subject	Chemistry; Medicine, Health and Life Sciences
Keyword	Chromatin, Transcription factor, Single-nucleotide polymorphism, Transcriptome, Gene, Regulation of gene expression, Expression quantitative trait loci, Gene expression
License/Data Use Agreement	CC BY 4.0


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Persistent Identifier	perma:LIST.BD4ORK
Publication Date	2026-07-06
Title	Identification of Parkinson’s disease-associated regulatory variants in human dopaminergic neurons reveals modulators of SCARB2 and BAG3 expression [* Cross-Reference *]
Other Identifier	https://doi.org/10.64898/2026.03.26.714241 OpenAlex ID: https://openalex.org/W7141733681
Author	Déborah Gérard (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0002-6083-6614 Jochen Ohnmacht (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0001-7109-6802 Borja Gomez Ramos (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0002-7353-2943 Marie Catillon (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) Jafar Sharif (RIKEN Center for Integrative Medical Sciences) - ORCID: https://orcid.org/0000-0003-0422-3597 Nina Baumgarten (Goethe University Frankfurt, German Center for Infection Research, German Centre for Cardiovascular Research) - ORCID: https://orcid.org/0000-0002-5423-8634 Dennis Hecker (Goethe University Frankfurt, German Center for Infection Research, German Centre for Cardiovascular Research) - ORCID: https://orcid.org/0000-0003-0272-243X Aurélien Ginolhac (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0001-7665-9547 Zied Landoulsi (Luxembourg Institute of Health) - ORCID: https://orcid.org/0000-0002-2327-3904 Elena Valceschini (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0009-0007-9322-6357 Aleksandar Raković (University of Lübeck) - ORCID: https://orcid.org/0000-0002-8127-7911 Christine Klein (University of Lübeck) Patrick May (University of Luxembourg) Haruhiko Koseki (Chiba University, RIKEN Center for Integrative Medical Sciences) Marcel H. Schulz (Goethe University Frankfurt, German Center for Infection Research, German Centre for Cardiovascular Research) Thomas Sauter (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0001-8225-2954 Rejko Krüger (Centre Hospitalier de Luxembourg, University of Luxembourg, Luxembourg Institute of Health) Lasse Sinkkonen (University of Luxembourg, Luxembourg Institute of Health, Luxembourg Institute of Science and Technology) - ORCID: https://orcid.org/0000-0002-4223-3027
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Description	Abstract A hallmark of Parkinson’s disease (PD) is the degeneration of midbrain dopaminergic neurons (mDANs). Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with PD, but causal variants and mechanisms remain unknown. Many PD-associated SNPs reside in regulatory regions, where they may disrupt transcription factor binding sites (TFBS) and alter gene expression. To assess how non-coding PD SNPs affect gene regulation in mDANs, we identify variants predicted to alter TF binding and functionally validate their effects in a cell type-specific context. We integrate time-series transcriptome and chromatin accessibility data from iPSC-derived neurons with chromatin topology and genetic variants. We profile 3D chromatin conformation in neuronal progenitors (smNPCs) and mDANs using LowC, identifying changes in A/B compartments and topologically associated domains. PD SNPs are enriched near genes expressed in mDANs, and we predict 254 regulatory variants that create or disrupt TFBS. Using chromatin conformation data, we link variants to target genes. At the BAG3 and SCARB2 loci, reporter assays in mDANs show reduced transcription driven by PD-associated alleles. Knock-down of NR2C2, a putative SCARB2 regulator, increases SCARB2 expression in differentiating neurons. The PD-associated SCARB2 allele shows reduced chromatin accessibility in mDANs and is associated with decreased expression in brain eQTL data. Insertion of PD-associated BAG3 allele by prime editing reduces chromatin accessibility across cell types, consistent with altered binding of LIM-homeodomain transcription factors. Together, these results prioritize functional PD SNPs and show that variants at SCARB2 and BAG3 modulate gene expression in mDANs, providing mechanistic insight into PD. (2026-03-27) *This entry has been automatically imported via OpenAlex by LIST harvest scripts. Please refer to https://doi.org/10.64898/2026.03.26.714241 for the original and latest version of the publication* (2026-07-01)
Subject	Chemistry; Medicine, Health and Life Sciences
Keyword	Chromatin Transcription factor Single-nucleotide polymorphism Transcriptome Gene Regulation of gene expression Expression quantitative trait loci Gene expression
Topic Classification	Genomics and Chromatin Dynamics Nuclear Receptors and Signaling Parkinson's Disease Mechanisms and Treatments
Deposit Date	2026-03-27
Data Type	Preprint
Data Source	bioRxiv (Cold Spring Harbor Laboratory)

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