Genome-wide association study reveals genetic risk underlying Parkinson's disease

Simón‐Sánchez, Javier; Schulte, Claudia; Brás, José; Sharma, Manu; Gibbs, J. Raphael; Berg, Daniela; Paisán-Ruı́z, Coro; Lichtner, Peter; Scholz, Sonja W.; Hernandez, Dena G.; Krüger, Rejko; Federoff, Monica; Klein, Christine; Goate, Alison M.; Perlmutter, Joel S.; Bonin, Michael; Nalls, Michael A.; Illig, Thomas; Gieger, Christian; Houlden, Henry; Steffens, Michael; Okun, Michael S.; Racette, Brad A.; Cookson, Mark; Foote, Kelly D.; Fernández, Hubert H.; Traynor, Bryan J.; Schreiber, Stefan; Arepalli, Sampath; Zonozi, Ryan R.; Gwinn‐Hardy, Katrina; Brug, Marcel van der; Lopez, Grisel; Chanock, Stephen J.; Schatzkin, Arthur; Park, Yikyung; Hollenbeck, Albert R.; Gao, Jianjun; Huang, Xuemei; Wood, Nicholas W.; Lorenz, Delia; Deuschl, Günther; Chen, Honglei; Rieß, Olaf; Hardy, John; Singleton, Andrew B.; Gasser, Thomas

doi:10.1038/ng.487

Cited by 1,767 publications

(1,581 citation statements)

References 22 publications

Supporting

Mentioning

1,498

Contrasting

Unclassified

Order By: Relevance

“…15,18 Remarkable, two recent GWASs in PD showed association between variants located in the 3 0 end of SNCA and PD. 5,6 Yet, the nature of these regulatory variants/mutations remains to be elucidated. We sought to identify variants in the 3 0 UTR of SNCA that might be responsible for a differential regulation in PD patients.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…4 Recent genome-wide association studies in PD pointed to the 3 0 end of SNCA, which had already been implicated in the regulation of SNCA expression. [5][6][7] The 3 0 untranslated region (UTR) of SNCA carries various putative microRNA (miRNA) -binding sites that could have a role in SNCA expression and thus contribute to the susceptibility to develop PD. 8,9 We hypothesized that variants located within the 3 0 UTR might influence the expression of SNCA by modulating translation or mRNA stability.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2012

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4] Neuropathologically, the overlap is exemplified by the coexistence of hallmark features of both Alzheimer's disease (AD) and PD in individuals with Lewy body disease. 1 On the genetic level, common genetic variants in microtubule-associated protein tau (MAPT) represent risk factors for PD 3,4 whereas, at the same time, rare variants of strong effect in MAPT have long been recognized as a cause of frontotemporal dementia (FTD). 2 Phenotypically, it is known that at least 30% of individuals with PD develop dementia 5,6 and that age has been described as a major predisposing factor for the development of cognitive impairment.…”

Section: Introductionmentioning

confidence: 99%

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

et al. 2015

Self Cite

View full text Add to dashboard Cite

Many individuals with Parkinson's disease (PD) develop cognitive deficits, and a phenotypic and molecular overlap between neurodegenerative diseases exists. We investigated the contribution of rare variants in seven genes of known relevance to dementias (β-amyloid precursor protein (APP), PSEN1/2, MAPT (microtubule-associated protein tau), fused in sarcoma (FUS), granulin (GRN) and TAR DNA-binding protein 43 (TDP-43)) to PD and PD plus dementia (PD+D) in a discovery sample of 376 individuals with PD and followed by the genotyping of 25 out of the 27 identified variants with a minor allele frequency o5% in 975 individuals with PD, 93 cases with Lewy body disease on neuropathological examination, 613 individuals with Alzheimer's disease (AD), 182 cases with frontotemporal dementia and 1014 general population controls. Variants identified in APP were functionally followed up by Aβ mass spectrometry in transiently transfected HEK293 cells. PD+D cases harbored more rare variants across all the seven genes than PD individuals without dementia, and rare variants in APP were more common in PD cases overall than in either the AD cases or controls. When additional controls from publically available databases were added, one rare variant in APP (c.1795G4A(p.(E599K))) was significantly associated with the PD phenotype but was not found in either the PD cases or controls of an independent replication sample. One of the identified rare variants (c.2125G4A (p.(G709S))) shifted the Aβ spectrum from Aβ40 to Aβ39 and Aβ37. Although the precise mechanism remains to be elucidated, our data suggest a possible role for APP in modifying the PD phenotype as well as a general contribution of genetic factors to the development of dementia in individuals with PD.

show abstract

“…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

Self Cite

125

View full text Add to dashboard Cite

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

show abstract

Genome-wide association study reveals genetic risk underlying Parkinson's disease

Cited by 1,767 publications

References 22 publications

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

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

Rare variants in β-Amyloid precursor protein (APP) and Parkinson’s disease

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

Contact Info

Product

Resources

About