title: Polygenic risk of Parkinson disease is correlated with disease age at onset.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, Cardiff University School of Medicine, Cardiff, United Kingdom.
authors.forename: Valentina
authors.initials: V
authors.lastname: Escott-Price
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.forename: Steven
authors.initials: S
authors.lastname: Lubbe
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D010300:Parkinson Disease / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors