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

Escott-Price, Valentina, Nalls, Mike A., Morris, Huw R., Lubbe, Steven, Brice, Alexis, Gasser, Thomas, Heutink, Peter, Wood, Nicholas W., Hardy, John, Singleton, Andrew B. and Williams, Nigel Melville 2015. Polygenic risk of Parkinson disease is correlated with disease age at onset. Annals of Neurology 77 (4) , pp. 582-591. 10.1002/ana.24335

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Abstract

OBJECTIVE: We 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. METHODS: This 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. RESULTS: Our 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). INTERPRETATION: This 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley-Blackwell
ISSN: 0364-5134
Date of Acceptance: 7 December 2014
Last Modified: 21 Jun 2019 20:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/81561

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