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. 2015 Apr;77(4):582-91.
doi: 10.1002/ana.24335. Epub 2015 Mar 13.

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

Valentina Escott-Price  1 ; International Parkinson's Disease Genomics Consortium; Mike A Nalls, Huw R Morris, Steven Lubbe, Alexis Brice, Thomas Gasser, Peter Heutink, Nicholas W Wood, John Hardy, Andrew B Singleton, Nigel M Williams; IPDGC consortium members
Affiliations

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

Valentina Escott-Price et al. Ann Neurol. 2015 Apr.

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.

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Figures

Figure 1
Figure 1
Assessment of the level that polygenic scores > 0 are enriched in Parkinson disease patients with age at onset (AAO) < 40 years compared to AAO > 80 years. *p < 0.05, **p < 0.01, ***p < 0.001. OR = odds ratio; SD = standard deviation; SNP = single nucleotide polymorphism.
Figure 2
Figure 2
Assessment of the level that polygenic scores > 1.5 are enriched in different thresholds of early versus late onset Parkinson disease patients. *p < 0.05, **p < 0.01, ***p < 0.001. OR = odds ratio; SNP = single nucleotide polymorphism.
Figure 3
Figure 3
Assessment of the level that polygenic scores > 1.5 are enriched in different thresholds of early versus late onset Parkinson disease (PD) patients when 18 regions reported to be associated with PD are excluded. *p < 0.05, **p < 0.01, ***p < 0.001. OR = odds ratio; SNP = single nucleotide polymorphism.
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