Journal
ANNALS OF NEUROLOGY
Volume 77, Issue 4, Pages 582-591Publisher
WILEY
DOI: 10.1002/ana.24335
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Funding
- Parkinson's UK [K0906, 8047, J-0804]
- Department of Health National Institute for Health Research Biomedical Research Centre
- Medical Research Council [G0700943]
- German National Genome Network (German Ministry for Education and Research) [01GS08134]
- German Center for Neurodegenerative Diseases
- NIH Intramural Research Program of the National Institute on Aging, Department of Health and Human Services [Z01 AG000949-06, Z01 AG000950-10]
- French National Agency of Research [ANR-08-MNP-012]
- National Research Funding Agency [ANR-08-NEUR-004-01]
- Hersenstichting Nederland
- Neuroscience Campus Amsterdam
- Section of Medical Genomics, Prinses Beatrix Fonds
- MRC [MR/L023784/2, G1100643, MC_G1000735, G0700943] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PhD2014-16] Funding Source: researchfish
- Medical Research Council [MC_G1000735, MR/L501554/1, G0700943, MR/L010305/1, MR/L023784/2, G1100643] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0507-10376, NF-SI-0513-10064] Funding Source: researchfish
- Parkinson's UK [G-0612, J-0804, G-0907] Funding Source: researchfish
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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 x 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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