Genome-wide association study confirms extant PD risk loci among the Dutch

Simón‐Sánchez, Javier; Hilten, Jacobus J. van; Warrenburg, Bart van de; Post, Bart; Berendse, Henk W.; Arepalli, Sampath; Hernandez, Dena G.; Bie, Rob M.A. de; Velseboer, Daan C.; Scheffer, Hans; Bloem, B.R.; Dijk, Karin D. van; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, André G.; Rizzu, Patrizia; Bochdanovits, Zoltán; Singleton, Andrew B.; Heutink, Peter

doi:10.1038/ejhg.2010.254

Cited by 167 publications

(144 citation statements)

References 68 publications

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“…8C) were declared for genes where, at minimum, knockdown by half of all same-gene targeting siRNAs yielded a non-toxicity-associated Ϯ25% change in ␣-synuclein concentration in both the re-test (SynBa2-Tb/SynBa3-d2) and orthogonal (hSA5.1-Tb/SynBa2-d2) focused screens. It is noteworthy that of these kinases, the DGKQ locus has repeatedly been identified as a PD risk factor (37)(38)(39)(40). Western blotting was used to validate two of the hits.…”

Section: Figure 3 Determination Of ␣-Synuclein Tr-fret Assay Specifimentioning

confidence: 99%

Novel One-step Immunoassays to Quantify α-Synuclein

Bidinosti

Shimshek

Mollenhauer

et al. 2012

Journal of Biological Chemistry

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Background: Robust assays for ␣-synuclein quantification are essential for Parkinson disease therapeutic development. Results: TR-FRET immunoassays were validated for total and oligomeric ␣-synuclein and used to screen small molecules and kinases that regulate ␣-synuclein expression. Conclusion: TR-FRET immunoassays are suitable for biomarker development and high-throughput screening. Significance: This is the first platform for large-scale drug discovery and for neuronal pathway analysis of ␣-synuclein expression regulation.

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Section: Figure 3 Determination Of ␣-Synuclein Tr-fret Assay Specifimentioning

confidence: 99%

Novel One-step Immunoassays to Quantify α-Synuclein

Bidinosti

Shimshek

Mollenhauer

et al. 2012

Journal of Biological Chemistry

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“…Recently, our understanding of idiopathic PD has been enhanced by genome‐wide association (GWA) studies6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 that have collectively identified PD risk variants at >18 loci 6, 7. Despite their high levels of significance, these 18 loci are thought to account for only a very small amount (3–5%) of the expected heritability of PD 17.…”

mentioning

confidence: 99%

Polygenic risk of Parkinson disease is correlated with disease age at onset

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

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122

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ObjectiveWe have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.MethodsThis study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta‐analysis of PD genome‐wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.ResultsOur polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome‐wide association cohorts (minimum p = 3.76 × 10−6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).InterpretationThis provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes. Ann Neurol 2015;77:582–591

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“…9,10 Here we aim to detect the known location of the REP1 variant in a recent PD GWAS data set. 5 In this study, the most strongly associated SNP on chromosome 4 was rs2736990 inside SNCA (P ¼ 8.1 Â 10 À6 ). The pattern of the single SNP associations did not clearly point to a particular position within the SNCA gene, instead the top four most strongly associated SNPs were 360 kb apart and were located in several adjacent LD blocks of a total length ofB600 kb (Figure 3).…”

Section: Localization Of Causal Variantmentioning

confidence: 52%

“…Only subjects consented for the General Research Use were included. For a detailed description of the samples and genotyping see 5 (PD data) and dbGaP (phs000168.v1.p1; AD data).…”

Section: Methodsmentioning

confidence: 99%

Accurate prediction of a minimal region around a genetic association signal that contains the causal variant

et al. 2013

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In recent years, genome-wide association studies have been very successful in identifying loci for complex traits. However, typically these findings involve noncoding and/or intergenic SNPs without a clear functional effect that do not directly point to a gene. Hence, the challenge is to identify the causal variant responsible for the association signal. Typically, the first step is to identify all genetic variation in the locus region, usually by resequencing a large number of case chromosomes. Among all variants, the causal one needs to be identified in further functional studies. Because the experimental follow up can be very laborious, restricting the number of variants to be scrutinized can yield a great advantage. An objective method for choosing the size of the region to be followed up would be highly valuable. Here, we propose a simple method to call the minimal region around a significant association peak that is very likely to contain the causal variant. We model linkage disequilibrium (LD) in cases from the observed single SNP association signals, and predict the location of the causal variant by quantifying how well this relationship fits the data. Simulations showed that our approach identifies genomic regions of on average B50 kb with up to 90% probability to contain the causal variant. We apply our method to two genome-wide association data sets and localize both the functional variant REP1 in the a-synuclein gene that conveys susceptibility to Parkinson's disease and the APOE gene responsible for the association signal in the Alzheimer's disease data set.

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Genome-wide association study confirms extant PD risk loci among the Dutch

Cited by 167 publications

References 68 publications

Novel One-step Immunoassays to Quantify α-Synuclein

Novel One-step Immunoassays to Quantify α-Synuclein

Polygenic risk of Parkinson disease is correlated with disease age at onset

Accurate prediction of a minimal region around a genetic association signal that contains the causal variant

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