Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson’s disease etiology

Coetzee, Simon; Pierce, Steven; Brundin, Patrik; Brundin, Lena; Hazelett, Dennis J.; Coetzee, Gerhard A.

doi:10.1038/srep30509

Cited by 51 publications

(46 citation statements)

References 65 publications

(83 reference statements)

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“…With these results in mind, it is tempting to speculate that PD presents genetically as more of a systemic disorder, with a bias to brain pathology, as opposed to a primary brain disorder. In support of this view, PD-associated risk variants have been found associated with monocytes and the innate immune system 13,40,41 , in addition to lymphocytes, mesendoderm, liver-and fat-cells 42 . Recent work has also demonstrated a causal relationship between BMI and PD 43 , which together with the repurposing of exenatide (a glucagon-like peptide-1 receptor agonist currently licensed for the treatment of type 2 diabetes) for the potential treatment of PD 44 , highlights the need to look beyond the brain and selective neuronal vulnerability.…”

Section: Discussionmentioning

confidence: 83%

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

Reynolds

Botía

Nalls

et al. 2018

Preprint

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Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-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. URLsBarres immunopanning,

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Section: Discussionmentioning

confidence: 83%

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

Reynolds

Botía

Nalls

et al. 2018

Preprint

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“…This is a common dilemma, as a majority of risk variants identified in GWASs over the past 2 decades are not associated with coding changes in expressed proteins. 32 Furthermore, disease-associated intronic SNPs can regulate the expression of more distant genes. When referring to BRAINEAC and GTEx, rs564309 was found not to be a brain eQTL at distant genes outside of our region of interest.…”

Section: Discussionmentioning

confidence: 99%

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Jabbari

Woodside

Tan

et al. 2018

Annals of Neurology

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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.MethodsTwo independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson syndrome (RS) and non‐RS groups. We carried out separate logistic regression GWASs 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/coexpression patterns of our identified genes and used our data to carry out gene‐based association testing.ResultsOur lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome‐wide significance in our whole cohort analysis (odds ratio = 5.5, 95% confidence interval = 3.2–10.0, p = 1.7 × 10−9). 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.InterpretationOur 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. Ann Neurol 2018;84:485–496

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“…In addition, many LRRK2-coding variants are associated with PD risk, including G2385R and R1628P, which confer increased risk in Asian populations, whereas a N551K-R1398H haplotype may confer a protective effective [8,9]. Genome-wide association studies have also identified common variants (or single nucleotide polymorphisms) at the LRRK2 locus that increase risk for idiopathic PD, although it is not yet clear how these SNPs that are enriched in gene regulatory regions influence LRRK2 expression in different tissues [5,10]. G2019S represents the most frequent mutation being found in 5–6% of familial and 1–2% of idiopathic PD cases in the US population, and in up to 40% of cases in certain ethnicities [4].…”

Section: Leucine-rich Repeat Kinase 2 and Parkinson’s Diseasementioning

confidence: 99%

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

Islam

Moore

2017

Biochemical Society Transactions

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson’s disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity. Familial mutations influence both of these enzymatic activities, suggesting that they may be important for the development of PD. Many LRRK2 models have been established to understand the pathogenic effects and mechanisms of familial mutations. Here, we provide a focused discussion of the evidence supporting a role for kinase and GTPase activity in mediating the pathogenic effects of familial LRRK2 mutations in different model systems, with an emphasis on rodent models of PD. We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring LRRK2 mutations, to neurodegeneration in LRRK2 rodent models. We aim to provide a clear and unbiased review of some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

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Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson’s disease etiology

Cited by 51 publications

References 65 publications

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

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

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

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