Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease

Satake, Wataru; Nakabayashi, Yasuo; Mizuta, Ikuko; Hirota, Yushi; Ito, Chiyomi; Kubo, Michiaki; Kawaguchi, Takahisa; Tsunoda, Tatsuhiko; Watanabe, Masahiko; Takeda, Atsushi; Tomiyama, Hiroyuki; Nakashima, Kenichiro; Hasegawa, Kazuko; Obata, Fumiya; Yoshikawa, Takeo; Kawakami, Hideshi; Sakoda, Saburo; Yamamoto, Mitsutoshi; Hattori, Nobutaka; Murata, Miho; Nakamura, Yusuke; Toda, Tatsushi

doi:10.1038/ng.485

Cited by 1,190 publications

(633 citation statements)

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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.…”

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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

125

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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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confidence: 99%

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

Escott‐Price¹,

Nalls

Morris

et al. 2015

Annals of Neurology

125

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“…Missense mutations and locus multiplications in the SNCA gene, which encodes the protein α-synuclein, have been found to cause familial forms of PD. [1][2][3][4][5] Genome wide association studies (GWAS) have shown that polymorphisms in the SNCA gene are risk factors for developing sporadic PD [6][7][8][9] and aggregated α-synuclein is the main component of Lewy bodies, the protein inclusions prevalent in the brains of patients with PD. 10 Furthermore, overexpression of α-synuclein has been found to be toxic to dopaminergic neurons, implicating α-synuclein as a key player in the molecular mechanisms of the disease.…”

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Loss of MicroRNA-7 Regulation Leads to α-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo

et al. 2017

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General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/pure/about/ebr-terms show that miR-7 is decreased in the substantia nigra of patients with PD and therefore may play an essential role in the regulation of α-synuclein expression. Furthermore, we have found that lentiviral mediated expression of miR-7 complementary binding sites to stably induce a loss of miR-7 function results in an increase in α-synuclein expression in vitro and in vivo. We have also shown that depletion of miR-7 using a miR-decoy produces a loss of nigral dopaminergic neurons accompanied by a reduction of striatal dopamine content. These data suggest that miR-7 has an important role in the regulation of α-synuclein and dopamine physiology and may provide a new paradigm to study the pathology of PD.3

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“…Two recent genome-wide association studies on PD found that a common variant in five genes, including ␣-synuclein and MAPT, which increase disease susceptibility (31,32). Moreover, an earlier study indicated that the cognitive decline and development of PD dementia is strongly associated with a synergistic interaction between the MAPT inversion polymorphism and a single nucleotide polymorphism on the ␣-synuclein gene (33).…”

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confidence: 99%