Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

Spencer, Chris C. A.; Plagnol, Vincent; Strange, Amy; Gardner, Michelle; Paisán-Ruı́z, Coro; Band, Gavin; Barker, Roger A.; Bellenguez, Céline; Bhatia, Kailash P.; Blackburn, Hannah; Blackwell, J. M.; Bramon, Elvira; Brown, Martin A.; Brown, Matthew A.; Burn, David; Casas, Juan-Pablo; Chinnery, Patrick F.; Clarke, Carl E; Corvin, Aiden; Craddock, Nicholas John; Deloukas, Panos; Edkins, Sarah; Evans, Jonathan; Freeman, Colin; Gray, Emma; Hardy, John; Hudson, Gavin; Hunt, Sarah; Jankowski, Janusz; Langford, Cordelia; Lees, Andrew J.; Markus, Hugh S.; Mathew, Christopher G.; McCarthy, Mark I.; Morrison, Karen; Palmer, Colin N.A.; Pearson, Justin; Peltonen, Leena; Pirinen, Matti; Plomin, Robert; Potter, Simon; Rautanen, Anna; Sawcer, Stephen; Su, Zhan; Trembath, Richard C.; Viswanathan, Ananth C.; Williams, Nigel; Morris, Huw; Donnelly, Peter; Wood, Nicholas W.

doi:10.1093/hmg/ddq469

Cited by 196 publications

(140 citation statements)

References 30 publications

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“…Polygenic score analysis revealed significant evidence for an overall enrichment of the PD score alleles identified in the UK GWA discovery sample14 in the cases of each of 3 independent PD GWA cohorts from the USA (×2) and Germany (Table 1). …”

Section: Resultsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

“…The age at onset (AAO) of PD has a relatively high heritability19 and has been previously shown to be associated with a small number of common variants,14, 20 some of which are strongly associated with disease 14. Using polygenic score analysis, we have considered PD according to a liability threshold model.…”

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confidence: 99%

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

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

122

View full text Add to dashboard Cite

show abstract

“…However, our results indicate that this genomic fragment does not carry mutations associated with the 3 0 signals found in association studies on PD. 5,6,20 Interestingly, detailed analysis of the SNCA locus revealed evidence for an additional independent association signal located upstream of exon 1 of SNCA. 20 Thus, several linkage disequilibrium (LD) blocks may exist within the SNCA locus carrying the association signals.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,20 Interestingly, detailed analysis of the SNCA locus revealed evidence for an additional independent association signal located upstream of exon 1 of SNCA. 20 Thus, several linkage disequilibrium (LD) blocks may exist within the SNCA locus carrying the association signals. Identification of these LD blocks will help to determine which regions of SNCA carries the causative variant for PD.…”

Section: Discussionmentioning

confidence: 99%

Variants in the 3′UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression

et al. 2012

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Alpha-synuclein (SNCA) is a major risk gene for Parkinson's disease (PD) and increased SNCA gene dosage results in a parkinsonian syndrome in affected families. Regulatory regions relevant for SNCA expression include the 3 0 untranslated region (UTR), which among other regulatory elements contains several micro-RNA-binding sites. Interestingly, variants located in the 3 0 region of SNCA have been associated with PD in two genome-wide association studies. To test whether private mutations in this region contribute to PD, we sequenced the 3 0 UTR of SNCA in 1285 PD patients and 1120 age/sex-matched healthy controls. We found two rare variants, the one corresponding to the single nucleotide polymorphism rs145304567 and the novel variant c.*1004_1008delTTTTT. Although rs145304567 affects the putative-binding site of microRNA (miRNA) -433, the allele distribution was similar in PD patients and controls, and the expression of SNCA mRNA was not related to the genotype. Furthermore, a regulatory effect of miRNA-433 on SNCA expression levels was not detected.

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Association of Sequence Alterations in the Putative Promoter of <emph type="ital">RAB7L1</emph> With a Reduced Parkinson Disease Risk

Gan‐Or¹

2012

Arch Neurol

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Subjects: Five single-nucleotide polymorphisms (SNPs) located between RAB7L1 and SLC41A1 were analyzed in 720 patients with PD and 642 controls, all of Ashkenazi Jewish origin.Main Outcome Measures: Haplotypes were defined and risk estimates were determined for each SNP and haplotype. Bioinformatic analysis defined the putative promoter region of RAB7L1 and the transcription factor binding sites that are potentially affected by 2 of the tested SNPs.Results: All tested SNPs were significantly associated with PD (odds ratios=0.64-0.76; P=.0002-.014). Two of them, rs1572931 and rs823144, were localized to the putative promoter region of RAB7L1 and their sequence variations al-teredthepredictedtranscriptionfactorbindingsitesofCdxA, p300, GATA-1, Sp1, and c-Ets-1. Only 0.4% of patients were homozygous for the protective rs1572931 genotype (T/T), compared with 3.0% among controls (P=5ϫ10 −5 ). This SNP was included in a haplotype that reduced the risk for PD by 10-to 12-fold (P=.002-.01) in all patients with PD and in a subgroupofpatientswhodonotcarrytheAshkenazifounder mutations in the GBA or LRRK2 genes.Conclusions: Our data demonstrate that specific SNP variations and haplotypes in the PARK16 locus are associated with reduced risk for PD in Ashkenazim. Although it is possible that alterations in the putative promoter of RAB7L1 are associated with this effect, the role of other genes in this locus cannot be ruled out.

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Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21

Cited by 196 publications

References 30 publications

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

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

Variants in the 3′UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression

Association of Sequence Alterations in the Putative Promoter of <emph type="ital">RAB7L1</emph> With a Reduced Parkinson Disease Risk

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