A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Chang, Diana; Nalls, Mike A.; Hallgrímsdóttir, Ingileif B.; Hu, Michele T.M.; Brug, Marcel van der; Cai, Fang; Kerchner, Geoffrey A.; Ayalon, Gai; Bingol, Baris; Sheng, Morgan; Hinds, David A.; Behrens, Timothy W.; Singleton, Andrew B.; Bhangale, Tushar; Graham, Robert

doi:10.1038/ng.3955

Cited by 1,031 publications

(1,127 citation statements)

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“…The major limitation of our study is that our cohort size was relatively small compared to case–control GWAS in PSP15 and other neurodegenerative diseases 30, 31. Further replication of our findings in larger cohorts is desirable, including other non‐RS phenotypes such as PSP‐F, to confirm the role of TRIM11 and identify genetic determinants of clinical phenotype in PSP at other loci.…”

Section: Resultsmentioning

confidence: 91%

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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Section: Resultsmentioning

confidence: 91%

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Jabbari

Woodside

Tan

et al. 2018

Annals of Neurology

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“…Second, SN neurons containing the calcium-buffering protein calbindin 1 (CALB1) were relatively more resistant to neurodegeneration compared to CALB1-negative neurons [19]. Third, inositol triphosphate kinase B (ITPKB), a critical regulator of the IP3/Ca2+ signaling pathway, was identified as a novel PD gene candidate(s) in a recent large genome wide association study [20]. Altered ITPKB gene expression was also reported in the postmortem brains of Alzheimer's disease patients [21].…”

Section: Discussionmentioning

confidence: 99%

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Zimering¹

2018

JED

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Aims: To test whether circulating neurotoxic autoantibodies increase in adult type 2 diabetes mellitus with Parkinson's disease (PD) or dementia. To identify the G-protein coupled receptor on neuroblastoma cells mediating neural inhibitory effects in diabetic Parkinson's disease plasma autoantibodies. To determine the mechanism of accelerated neuroblastoma cell death and acute neurite retraction induced by diabetic Parkinson's disease and dementia autoantibodies.Methods: Protein-A eluates from plasma of twelve older adult male diabetic patients having Parkinson's disease (n=10) or dementia (n=2), and eight age-matched control diabetic patients were tested for ability to cause accelerated N2A neuroblastoma cell death and acute neurite retraction. Specific antagonists of G protein coupled receptors belonging to the G alpha q subfamily of heterotrimetric G-proteins, the phospholipase C/inositol triphosphate/Ca2+ pathway, or the RhoA/Rho kinase pathway were tested for ability to block diabetic Parkinson's disease/dementia autoantibodyinduced neurite retraction or N2A accelerated cell loss. Sequential Liposorber LA-15 dextran sulfate cellulose/protein-A affinity chromatography was used to obtain highly-purified fractions of diabetic Parkinson's disease autoantibodies .Results: Mean accelerated neuroblastoma cell loss induced by diabetic Parkinson's disease or dementia autoantibodies significantly exceeded (P = 0.001) the level of N2A cell loss induced by an identical concentration of the diabetic autoantibodies in control patients without these two comorbid neurodegenerative disorders. Co-incubation of diabetic Parkinson's disease and dementia autoantibodies with two-hundred nanomolar concentrations of M100907, a highly selective 5-HT2AR antagonist, completely prevented autoantibody-induced accelerated N2A cell loss and neurite retraction. A higher concentration (500 nM-10μM) of alpha-1 adrenergic, angiotensin II type 1, or endothelin A receptor antagonists did not substantially inhibit autoantibody-induced neuroblastoma cell death or prevent neurite retraction. Antagonists of the inositol triphosphate receptor (2-APB, 50μM), the intracellular calcium chelator (BAPTA-AM, 30 μM) and Y27632 (10 μM), a selective RhoA/Rho kinase inhibitor, each completely blocked acute neurite retraction induced by sixty nanomolar concentrations of diabetic Parkinson's disease autoantibodies. Co-incubation with 2-APB (1-2 μM) for 8 hours' prevented autoantibody-induced N2A cell loss. The highly-purified fraction obtained after Liposorber LA/protein-A affinity chromatography in hypertriglyceridemic diabetic dementia and Parkinson's disease plasmas had apparent MWs > 30 kD, and displayed enhanced N2A toxicity requiring substantially higher concentrations of 5-HT2AR antagonists (M100907, ketanserin, spiperone) to effectively neutralize. Conclusion:These data suggest increased autoantibodies in older adult diabetes with Parkinson's disease or dementia cause accelerated neuron loss via the 5-hydroxytryptamine 2 receptor coupled to ino...

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“…Later on, GWAS signals at SNCA showed an association with PD from intron 4 to after the 3′ UTR region (Simón-Sánchez et al 2009). Since then, SNCA has been overwhelmingly established in GWA studies identifying additional signals and providing further insights about the genetic risk at this locus (UK Parkinson’s Disease Consortium et al 2011; Lill et al 2012; Nalls et al 2014; Chang et al 2017). Current research suggests between 2 and 5 semi-independent association signals accounting for heritable risk at this locus (unpublished work, IPDGC).…”

Section: Common Risk Factors In Pdmentioning

confidence: 99%

“…Along the way, several GWAS (Edwards et al 2010; Hernandez et al 2012; Pihlstrøm et al 2013; International Parkinson Disease Genomics Consortium et al 2011; Satake et al 2009; Simón-Sánchez et al 2009; Lill et al 2012) and meta-analyses (Nalls et al 2014; Chang et al 2017) have been key at identifying common risk variability linked to genetically complex PD. To date, 43 loci have been associated at a genome-wide significant level with PD risk in individuals of European ancestry (Chang et al 2017).…”

Section: Identifying Risk Loci From Gwasmentioning

confidence: 99%

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Genetic risk factors in Parkinson’s disease

et al. 2018

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Over the last two decades, we have witnessed a revolution in the field of Parkinson’s disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.

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A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Cited by 1,031 publications

References 65 publications

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson’s Disease

Genetic risk factors in Parkinson’s disease

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