The Parkinson's Disease <scp>Genome‐Wide</scp> Association Study Locus Browser

Grenn, Francis P.; Kim, Jonggeol J.; Makarious, Mary B.; Iwaki, Hirotaka; Illarionova, Anastasia; Brolin, Kajsa; Kluss, Jillian H.; Schumacher-Schuh, Artur; Leonard, Hampton; Faghri, Faraz; Billingsley, Kimberley; Krohn, Lynne; Hall, Ashley; Díez-Fairén, Mónica; Periñán, María Teresa; Foo, Jia Nee; Sandor, Cynthia; Webber, Caleb; Fiske, Brian; Gibbs, J. Raphael; Nalls, Mike A.; Singleton, Andrew B.; Bandrés‐Ciga, Sara; Reed, Xylena; Blauwendraat, Cornelis

doi:10.1002/mds.28197

Cited by 76 publications

(86 citation statements)

References 70 publications

(115 reference statements)

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“…S3d) and its downregulation is associated with premature senescence in mouse models, cell cultures, and human brain tissue 36,37 . Lastly, DYRK1A is the top eQTL-nominated gene from our colocalization analysis, which aligns with prior eQTL-based gene nominations in this locus 21 . It is expressed in all brain cell types, but more so neurons than glia ( Fig.…”

Section: Resultssupporting

confidence: 80%

“…S1h-m ). When comparing our UCS SNPs to a subset of the FINEMAP results provided by Grenn and colleagues 21 (42 CS 95% SNPs across 18 loci), we found 10 overlapping SNPs, 6 of which were Consensus SNPs and 5 of which were also in our FINEMAP CS95%, across 9 loci (HIP1R, KRTCAP2, SH3GL2, SLC2A13, FAM47E-STBD1, TMEM175, TMEM163, CRHR1, and KCNS3). This limited concordance (10/42 SNPs = 23.8%) likely stems from several key methodological differences, including different LD panels and the fact that we specify a maximum of five causal SNPs for all loci whereas Grenn et al first estimated the number of independent causal signals in each locus using the stepwise model selection procedure in GCTA-COJO 22 .…”

Section: Resultsmentioning

confidence: 60%

“…To assess reproducibility, we also compared our FINEMAP results with those from a recent study that performed statistical fine-mapping (using FINEMAP) on the same PD GWAS meta-analysis dataset but using a TOPMed (n = 16,257 samples) as the LD reference panel 21 ( Fig. S1h-m ).…”

Section: Resultsmentioning

confidence: 99%

“…4a) . Previously, Grenn et al 21 used FINEMAP to nominate rs2248244 (the lead SNP) and rs11701722 as putative causal variants. Despite the aforementioned methodological differences, rs2248244 also appeared in our UCS.…”

Section: Resultsmentioning

confidence: 99%

“…h-m , Pairwise Spearman’s rank-order correlations between SNP-wise posterior probabilities generated by each of the fine-mapping methods used in this study with those of Grenn et al (generated using FINEMAP) 21 . Our FINEMAP results, as well results from the other tools we used (ABF, SuSiE, PolyFun+SuSiE) to a lesser degree, showed a strong and significant correlation with those of Grenn et al (Spearman’s rho = 0.68, p < 2.2×10 -16 ).…”

Section: Supplementary Figuresmentioning

confidence: 99%

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

Schilder

Raj

2020

Preprint

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Recent 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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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Supplementary Figuresmentioning

confidence: 99%

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

Schilder

Raj

2020

Preprint

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Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

Gjl

Humphrey

et al. 2021

Alzheimer's & Dementia

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Background Microglia are tissue‐resident macrophages of the central nervous system that are essential for homeostasis, immune response, neurogenesis, and neuronal plasticity. Genetic studies have strongly implicated microglial dysfunction in multiple neurodegenerative diseases. However, investigating genetically‐driven changes in gene expression in microglia has been limited by lack of access to these cells from the number of subjects required to perform well‐powered genomic analysis. Method Here we describe the transcriptome analysis of 255 primary human CD11b+ microglia samples isolated at autopsy from multiple brain regions of 100 human subjects with neurodegenerative and neuropsychiatric disorders. We performed systematic analyses to investigate various aspects of microglial heterogeneities including brain region, age, sex, and disease. By intersecting transcriptomics and genetics, we performed expression and splicing QTL analyses and by combining microglia from four different brain regions using a multivariate meta‐analysis method (mashR). Result We observed widespread transcriptome variation associated with microglia, suggesting that these genes may play important role in diversified responses to pathological stimuli of microglia at different locations. We also observed 1,693 genes (FDR < 0.05) whose expression is associated with age including many genes in Alzheimer’s (AD) (MS4A6A, FCER1G, and CR1) or Parkinson’s disease (PD) (BST1 and FCGR2A) GWAS loci. We identified 3,611 eQTLs (mashR local false sign rate < 0.05), of which 50% (1,791) show region‐specific effects. We identified over 300 eQTLs that colocalize with a known risk locus for a neurodegenerative or neuropsychiatric disease, nearly half of which are not found in prefrontal cortex or in peripheral monocytes. We prioritized 7 and 13 putative causal genes for AD and PD, respectively, many of which are novel genes (ITGAX, USP6NL, TSPOAP1, P2RY12, FCGR2C, and FGF20). Fine‐mapping of these colocalized loci with CNS chromatin accessibility (ATAC‐seq) and histone modification (H3K27ac) data nominates candidate causal variants that are within microglia‐specific enhancers and are likely to modify disease susceptibility by regulating gene expression and/or splicing in microglia. Conclusion In summary, we have built the most comprehensive catalog to date of genetic effects on the microglia transcriptome and propose molecular mechanisms of action of candidate functional variants in several neurological and neuropsychiatric diseases.

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Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis

Andersen

Bandrés‐Ciga

Reynolds

et al. 2021

Annals of Neurology

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Objective: Understanding 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. Methods: We used summary statistics from the most recent meta-analysis of genomewide 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. Results: We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 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 antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3. Interpretation: Our results provide further support for the importance of immune mechanisms in Parkinson's disease 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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The Parkinson's Disease Genome‐Wide Association Study Locus Browser

Cited by 76 publications

References 70 publications

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

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

Atlas of genetic effects in human microglia transcriptome across brain regions, aging and disease pathologies

Heritability Enrichment Implicates Microglia in Parkinson's Disease Pathogenesis

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