title: Whole-exome sequencing of 228 patients with sporadic Parkinson's disease.
abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of the population over 65 years characterized clinically by both motor and non-motor symptoms accompanied by the preferential loss of dopamine neurons in the substantia nigra pars compacta. Here, we sequenced the exomes of 244 Parkinson's patients selected from the Oxford Parkinson's Disease Centre Discovery Cohort and, after quality control, 228 exomes were available for analyses. The PD patient exomes were compared to 884 control exomes selected from the UK10K datasets. No single non-synonymous (NS) single nucleotide variant (SNV) nor any gene carrying a higher burden of NS SNVs was significantly associated with PD status after multiple-testing correction. However, significant enrichments of genes whose proteins have roles in the extracellular matrix were amongst the top 300 genes with the most significantly associated NS SNVs, while regions associated with PD by a recent Genome Wide Association (GWA) study were enriched in genes containing PD-associated NS SNVs. By examining genes within GWA regions possessing rare PD-associated SNVs, we identified RAD51B. The protein-product of RAD51B interacts with that of its paralogue RAD51, which is associated with congenital mirror movements phenotypes, a phenotype also comorbid with PD.
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sandor
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
authors.forename: Frantisek
authors.initials: F
authors.lastname: Honti
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Haerty
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom.
authors.forename: Konrad
authors.initials: K
authors.lastname: Szewczyk-Krolikowski
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Tomlinson
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Evetts
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Millin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Keane
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Shane A
authors.initials: SA
authors.lastname: McCarthy
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, West Wing Level 6, Headley Way, Oxford OX3 9DU, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Hu
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: Oxford Parkinson's Disease Centre, University of Oxford, Oxford, United Kingdom.|Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Wade-Martins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D000073359:Exome Sequencing
chemical_list: D004268:DNA-Binding Proteins; C413002:RAD51B protein, human