Establishing gene regulatory networks from Parkinson's disease risk loci

The latest meta-analysis of genome wide association studies (GWAS) identified 90 independent single nucleotide polymorphisms (SNPs) across 78 genomic regions associated with Parkinson's disease (PD), yet the mechanisms by which these variants influence the development of the disease remains largely elusive. To establish the functional gene regulatory networks associated with PD-SNPs, we utilised an approach combining spatial (chromosomal conformation capture) and functional (expression quantitative trait loci; eQTL) data. We identified 518 genes subject to regulation by 76 PD-SNPs across 49 tissues, that encompass 36 peripheral and 13 CNS tissues. Notably, one third of these genes were regulated via trans- acting mechanisms (distal; risk locus-gene separated by > 1Mb, or on different chromosomes). Of particular interest is the identification of a novel trans-eQTL-gene connection between rs10847864 and SYNJ1 in the adult brain cortex, highlighting a convergence between familial studies and PD GWAS loci for SYNJ1 (PARK20) for the first time. Furthermore, we identified 16 neuro-development specific eQTL-gene regulatory connections within the foetal cortex, consistent with hypotheses suggesting a neurodevelopmental involvement in the pathogenesis of PD. Through utilising Louvain clustering we extracted nine significant and highly intra-connected clusters within the entire gene regulatory network. The nine clusters are enriched for specific biological processes and pathways, some of which have not previously been associated with PD. Together, our results not only contribute to an overall understanding of the mechanisms and impact of specific combinations of PD-SNPs, but also highlight the potential impact gene regulatory networks may have when elucidating aetiological subtypes of PD.

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Single-cell epigenomic identification of inherited risk loci in Alzheimer’s and Parkinson’s disease

10.1101/2020.01.06.896159 ◽

2020 ◽

Cited By ~ 9

Author(s):

M. Ryan Corces ◽

Anna Shcherbina ◽

Soumya Kundu ◽

Michael J. Gloudemans ◽

Laure Frésard ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Single Cell ◽

Association Studies ◽

Regulatory Elements ◽

Brain Regions ◽

Chromatin Accessibility ◽

Adult Brain ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms

ABSTRACTGenome-wide association studies (GWAS) have identified thousands of variants associated with disease phenotypes. However, the majority of these variants do not alter coding sequences, making it difficult to assign their function. To this end, we present a multi-omic epigenetic atlas of the adult human brain through profiling of the chromatin accessibility landscapes and three-dimensional chromatin interactions of seven brain regions across a cohort of 39 cognitively healthy individuals. Single-cell chromatin accessibility profiling of 70,631 cells from six of these brain regions identifies 24 distinct cell clusters and 359,022 cell type-specific regulatory elements, capturing the regulatory diversity of the adult brain. We develop a machine learning classifier to integrate this multi-omic framework and predict dozens of functional single nucleotide polymorphisms (SNPs), nominating gene and cellular targets for previously orphaned GWAS loci. These predictions both inform well-studied disease-relevant genes, such as BIN1 in microglia for Alzheimer’s disease (AD) and reveal novel gene-disease associations, such as STAB1 in microglia and MAL in oligodendrocytes for Parkinson’s disease (PD). Moreover, we dissect the complex inverted haplotype of the MAPT (encoding tau) PD risk locus, identifying ectopic enhancer-gene contacts in neurons that increase MAPT expression and may mediate this disease association. This work greatly expands our understanding of inherited variation in AD and PD and provides a roadmap for the epigenomic dissection of noncoding regulatory variation in disease.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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Heritability enrichment implicates microglia in Parkinson’s disease pathogenesis

10.1101/2020.11.25.20238162 ◽

2020 ◽

Author(s):

Maren Stolp Andersen ◽

Sara Bandres-Ciga ◽

Regina H. Reynolds ◽

John Hardy ◽

Mina Ryten ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Cell Types ◽

Polygenic Risk Score ◽

Open Chromatin ◽

Specific Cell ◽

Genome Wide Association Studies ◽

Therapeutic Implications

AbstractObjectiveUnderstanding how different parts of the immune system contribute to pathogenesis in Parkinson’s disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson’s disease stratified by immune and brain cell types.MethodsWe used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson’s disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.ResultsWe found significant enrichment of Parkinson’s disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson’s disease association signal on chromosome 3.InterpretationOur results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson’s disease.

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Fine-mapping of Parkinson’s disease susceptibility loci identifies putative causal variants

10.1101/2020.10.22.340158 ◽

2020 ◽

Cited By ~ 1

Author(s):

Brian M. Schilder ◽

Towfique Raj

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Fine Mapping ◽

Disease Susceptibility ◽

Disease Risk ◽

Association Studies ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Causal Variants ◽

Underlying Mechanisms

AbstractRecent genome-wide association studies have identified 78 loci associated with Parkinson’s Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson’s-associated loci using four different statistical and functional fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disrupt LRRK2 and FCGR2A regulatory elements in microglia, MBNL2 enhancers in oligodendrocytes, and DYRK1A enhancers in neurons. Finally, we confirmed the functional relevance of fine-mapped SNPs using a suite of in silico validation approaches. Together, these results provide a robust list of likely causal variants underlying Parkinson’s Disease risk for further mechanistic studies.

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Linking common and rare disease genetics through gene regulatory networks

10.1101/2021.10.21.21265342 ◽

2021 ◽

Author(s):

Olivier B. Bakker ◽

Annique Claringbould ◽

Harm-Jan Westra ◽

Henry H. Wiersma ◽

Floranne Boulogne ◽

...

Keyword(s):

Gene Regulatory Networks ◽

Regulatory Networks ◽

Association Studies ◽

Genetic Diseases ◽

Common Disease ◽

Disease Genes ◽

Mendelian Disease ◽

Genome Wide Association Studies ◽

Gene Regulatory ◽

Key Genes

Genetic variants identified through genome-wide association studies (GWAS) are typically non-coding and exert small regulatory effects on downstream genes, but which downstream genes are ultimately impacted and how they confer risk remains mostly unclear. Conversely, variants that cause rare Mendelian diseases are often coding and have a more direct impact on disease development. We demonstrate that common and rare genetic diseases can be linked by studying the gene regulatory networks impacted by common disease-associated variants. We implemented this in the 'Downstreamer' method and applied it to 44 GWAS traits and find that predicted downstream "key genes" are enriched with Mendelian disease genes, e.g. key genes for height are enriched for genes that cause skeletal abnormalities and Ehlers-Danlos syndromes. We find that 82% of these key genes are located outside of GWAS loci, suggesting that they result from complex trans regulation rather than being impacted by disease-associated variants in cis. Finally, we discuss the challenges in reconstructing gene regulatory networks and provide a roadmap to improve identification of these highly connected genes for common traits and diseases.

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Genome-wide association studies of cognitive and motor progression in Parkinson's disease

10.1101/2020.05.07.20084343 ◽

2020 ◽

Author(s):

Manuela MX Tan ◽

Michael A Lawton ◽

Edwin Jabbari ◽

Regina H Reynolds ◽

Hirotaka Iwaki ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Age At Onset ◽

Case Control ◽

New Method ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide

Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies (GWASs) have identified variants associated with disease risk, but not progression. Objective: To identify genetic variants associated with PD progression in GWASs. Methods: We analysed three large, longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3,364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, where we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analysed in linear regressions in GWASs. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis. Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ϵ4 tagging variant, rs429358, was significantly associated with the rate of composite and cognitive progression in PD. No single variants were associated with motor progression. However in gene-based analysis, variation across ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (p=5.3 x 10^-6). Conclusions: This new method in PD improves measurement of symptom progression. We provide strong evidence that the APOE ϵ4 allele drives progressive cognitive impairment in PD. We have also reported loci of interest which need to be tested in further studies.

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Parkinson’s Disease Genetic Risk Evaluation in Microglia Highlights Autophagy and Lysosomal Genes

10.1101/2020.08.17.254276 ◽

2020 ◽

Author(s):

Alix Booms ◽

Steven E. Pierce ◽

Gerhard A. Coetzee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Cell Type ◽

Genome Wide ◽

Risk Snps ◽

A Cell ◽

Regulatory Dna

AbstractGenome-wide association studies (GWAS) have uncovered thousands of single nucleotide polymorphisms (SNPs) that are associated with Parkinson’s disease (PD) risk. The functions of most of these SNPs, including the cell type they influence, and how they affect PD etiology remain largely unknown. To identify functional SNPs, we aligned PD risk SNPs within active regulatory regions of DNA in microglia, a cell type implicated in PD development. Out of 6,749 ‘SNPs of interest’ from the most recent PD GWAS metanalysis, 73 were located in open regulatory chromatin as determined by both ATAC-seq and H3K27ac ChIP-seq. We highlight a subset of SNPs that are favorable candidates for further mechanistic studies. These SNPs are located in regulatory DNA at the SLC50A1, SNCA, BAG3, FBXL19, SETD1A, and NUCKS1 loci. A network analysis of the genes with risk SNPs in their promoters, implicated substance transport, involving autophagy and lysosomal genes. Our study provides a more focused set of risk SNPs and their associated risk genes as candidates for further follow-up studies, which will help identify mechanisms in microglia that increase the risk for PD.

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Reference SVA insertion polymorphisms are associated with dopaminergic degeneration in Parkinson’s Disease and differential gene expression in the PPMI cohort

10.21203/rs.3.rs-41600/v1 ◽

2020 ◽

Author(s):

Abigail L Pfaff ◽

Vivien J. Bubb ◽

John P. Quinn ◽

Sulev Koks

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Differential Gene Expression ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Sequencing Data ◽

Genome Wide ◽

Differential Gene

Abstract Background: The development of Parkinson’s disease (PD) involves a complex interaction of genetic and environmental factors. The majority of studies investigating the genetic component of complex diseases, including PD, have focused on single nucleotide polymorphisms as this enables genome wide analysis of a large number of samples. Genome wide association studies have been crucial in identifying PD risk variants, however a large proportion of the heritability of PD remains to be identified. To investigate the component of PD that may involve complex genetic variants we characterised SINE-VNTR-Alus (SVAs), a retrotransposon known to affect gene expression, in the Parkinson’s Progression Markers Initiative (PPMI) cohort.Results: Utilising whole genome sequencing from the PPMI cohort that consisted of 179 healthy controls, 371 individuals with PD and 58 individuals classified as SWEDD (scans without evidence of dopaminergic deficit) we genotyped SVAs in the reference genome for their presence or absence identifying 81 such SVAs. Seven of these SVAs were associated with progression of the disease, including four whose specific genotypes were linked to an increase in the gradient of dopaminergic loss when comparing the caudate to putamen from DaTscan imaging analysis. These seven SVAs also demonstrated regulatory properties as they were associated with differential gene expression in whole blood RNA sequencing data.Conclusion: This study highlights the importance of addressing variation of SVAs and potentially other types of retrotransposons in PD genetics, furthermore these SVA elements should be considered as regulatory domains that could play a role in disease progression.

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A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

10.1101/2021.03.08.21252688 ◽

2021 ◽

Author(s):

Anni Moore ◽

Sara Bandres-Ciga ◽

Cornelis Blauwendraat ◽

Monica Diez-Fairen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Age At Onset ◽

Brain Regions ◽

Whole Genome Sequencing Data ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Increased Risk

AbstractParkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. A recent finding has suggested an association between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to healthy individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

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