title: Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease.
abstract: Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49× coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease.
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Nino
authors.initials: N
authors.lastname: Spataro
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Calafell
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Cervera-Carles
authors.affiliation: Genomics Core Facility, Universitat Pompeu Fabra, Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Casals
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pagonabarraga
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Pascual-Sedano
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Antònia
authors.initials: A
authors.lastname: Campolongo
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain, Health Sciences Department, Universitat Oberta de Catalunya, Catalonia, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Kulisevsky
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Lleó
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain, National Institute for Bioinformatics (INB), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain and Center for Genomic Regulation (CRG), Barcelona Biomedical Research Park (PRBB), 08003 Barcelona, Spain.
authors.forename: Arcadi
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Department of Neurology, Institut d'Investigacions Biomèdiques Sant Pau-Hospital de Sant Pau, Universitat Autònoma de Barcelona, 08025 Barcelona, Spain, Center for Networking Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimón
authors.affiliation: Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain, elena.bosch@upf.edu.
authors.forename: Elena
authors.initials: E
authors.lastname: Bosch
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics