ArticleMolecular neurodegeneration2022
17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease are associated with LRRC37A/2 expression in astrocytes.
Article in Molecular neurodegeneration, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 54 citations in OpenAlex.
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- Single-cell expression QTL analyses of the human cerebellum reveal vulnerability of oligodendrocytes in essential tremor.Nature genetics · 2026Article
- Integrating Long-Read Structural Variant Analysis with single-nucleus RNA-seq to Elucidate Gene Expression Effects in Disease.bioRxiv : the preprint server for biology · 2026Article
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- Evolutionary hotspots of structural variation drive inter-individual differences in the expression of fusion transcripts in the human brain.Nucleic acids research · 2025Article
- Chr:17q21.31 locus risk haplotype H1 susceptibility to ferroptosis is mediated by endolysosomal pathway.Cell death & disease · 2025Article
- Transcriptomic Analysis of the Human Habenula in Schizophrenia.The American journal of psychiatry · 2025Article
- Long-read genome sequencing and multi-omics in aging and neurodegeneration.medRxiv : the preprint server for health sciences · 2025Article
- Structural variation, selection, and diversification of the NPIP gene family from the human pangenome.Cell genomics · 2025Article
- Inherited Genetic Variation in Parkinson's Disease: Convergence on Impaired Autophagosome-Lysosome Fusion Through the Altered Expression of mRNA Isoforms.Molecular neurobiology · 2025Article
- Identifying Key Plasma Proteins in the Onset of Parkinson's Disease: Proteome-Wide Mendelian Randomization and Single-Cell RNA Sequencing Analysis.Molecular neurobiology · 2025Article
- A map of enhancer regions in primary human neural progenitor cells using capture STARR-seq.Genome research · 2025Article
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21 authors at 8 institutions in 4 countries.
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Abstract
backgroundParkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified.
methodsTo better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue.
resultsWe identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue.
conclusionThese data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
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