Biology subjects

Feleke, R.

Publications and source records attributed to Feleke, R..

3 recordsLinked to original sources

bioRxiv2026

An overlooked distal regulatory signal on a shared haplotype drives the neuroinflammatory cascade underlying GBA1-associated Parkinson's disease

BACKGROUNDThe persistent puzzle of how GBA1 coding variants underlying monogenic Gaucher disease confer such strong risk for polygenic Parkinsons disease (PD) remains unresolved. Here, we sought to resolve this long-standing paradox. METHODSUsing the Parkinsons Progression Markers Initiative resource, we integrated whole-genome sequencing from sporadic PD cases and controls with matched transcriptomic, epigenomic and cerebrospinal fluid proteomic data across Northern European and Ashkenazi Jewish populations. Ancestry-specific genetic maps enabled precise integration of disease localisation with eQTL, pQTL and chromatin architecture, linking genetic association to molecular mechanism, while evolutionary genetic analyses resolved the regional haplotypic architecture. RESULTSWe identified a PD-associated regulatory signal located 150 kilobases distal to GBA1 that robustly replicated across all molecular datasets and both ancestries. Integrative mapping identified rs77268551-G as the candidate regulatory variant, which we show resides on an extended haplotype also carrying the Gaucher disease-causing N370S allele. Evolutionary analyses reveal a clear signature of recent positive selection acting on the Gaucher disease-causing N370S allele, giving rise to this extended shared haplotype that likely concealed the underlying distal PD-associated regulatory signal. rs77268551-G resides within a neuronal enhancer with features consistent with super-enhancer activity that orchestrates hierarchical enhancer-to-enhancer-to-promoter interactions with eleven cis-target genes, including ADAR, IL6R and GBA1, driving a coordinated transcriptional programme. Proteomic profiling identified genotype-specific cerebrospinal fluid protein signatures, including PARK7, BIN1 and SAA1, consistent with a neuroinflammatory programme. CONCLUSIONSThe findings support a dual-hit model in which a distal regulatory element is the primary driver of PD-associated molecular programmes, while co-inherited GBA1 protein-coding variation on the same haplotype modifies and amplifies the risk established by the regulatory variant, giving rise to the clinically distinct GBA1-associated PD phenotype. Regulatory activation and GBA1-related functional effects converge on neuroinflammatory and lysosomal pathways, and the resulting molecular signatures suggest genotype-linked biomarkers with potential clinical relevance.

genetics↗

bioRxiv2022

Single-cell Mendelian randomisation identifies cell-type specific genetic effects on human brain disease and behaviour

Translating genome-wide association loci to therapies requires knowledge of the causal genes, their directionality of effect and the cell-types in which they act. To infer these relationships in the human brain, we implemented Mendelian randomisation using single cell-type expression quantitative trait loci (eQTLs) as genetic anchors. Expression QTLs were mapped across 8 major cell-types in brain tissue exclusively ascertained from donors with no history of brain disease. We report evidence for a causal association between the change in expression of 118 genes and one or more of 16 brain phenotypes, revealing candidate targets for risk mitigation and opportunities for shared preventative therapeutic strategies. We highlight key causal genes for neurodegenerative and neuropsychiatric disease and for each, we report its cellular context and the therapeutic directionality required for risk mitigation. Our use of control samples establishes a new resource for the causal interpretation of GWAS risk alleles for human brain phenotypes.

neuroscience↗

bioRxiv2021

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy Body diseases

Parkinsons disease (PD), Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular "window" of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

neuroscience↗