Biology subjects

Reynolds, R. H.

Publications and source records attributed to Reynolds, R. H..

3 recordsLinked to original sources

bioRxiv2018

Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson’s disease heritability

Parkinsons disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of -synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set specifically expressed in astrocytic and microglial subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes to which cell types may have varying vulnerability.

genomics↗

bioRxiv2018

Genetic variability in response to Aβ deposition influences Alzheimer’s risk

Genetic analysis of late-onset Alzheimers disease risk has previously identified a network of largely microglial genes that form a transcriptional network. In transgenic mouse models of amyloid deposition we have previously shown that the expression of many of the mouse orthologs of these genes are co-ordinately up-regulated by amyloid deposition. Here we investigate whether systematic analysis of other members of this mouse amyloid-responsive network predicts other Alzheimers risk loci. This statistical comparison of the mouse amyloid-response network with Alzheimers disease genome-wide association studies identifies 5 other genetic risk loci for the disease (OAS1, CXCL10, LAPTM5, ITGAM and LILRB4). This work suggests that genetic variability in the microglial response to amyloid deposition is a major determinant for Alzheimers risk.\n\nOne Sentence SummaryIdentification of 5 new risk loci for Alzheimers by statistical comparison of mouse A{beta} microglial response with gene-based SNPs from human GWAS

neuroscience↗

bioRxiv2018

Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype

ObjectiveThe basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype.\n\nMethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardsons syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/co-expression patterns of our identified genes and used our data to carry out gene-based association testing.\n\nResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome wide significance in our whole cohort analysis - OR 5.5 (3.2-10.0), p-value 1.7x10-9. rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.\n\nInterpretationOur study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease modifying therapies.

neuroscience↗