title: An exome study of Parkinson's disease in Sardinia, a Mediterranean genetic isolate.
abstract: Parkinson's disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) ≥3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease.
authors.affiliation: Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000, CA, Rotterdam, The Netherlands.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Quadri
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cossu
authors.forename: Simone
authors.initials: S
authors.lastname: Olgiati
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Saddi
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Limei
authors.initials: L
authors.lastname: Ouyang
authors.forename: Jingchu
authors.initials: J
authors.lastname: Hu
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.forename: Josja
authors.initials: J
authors.lastname: Graafland
authors.forename: Valeria
authors.initials: V
authors.lastname: Ricchi
authors.forename: Daniela
authors.initials: D
authors.lastname: Murgia
authors.forename: Leonor Correia
authors.initials: LC
authors.lastname: Guedes
authors.forename: Claudio
authors.initials: C
authors.lastname: Mariani
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Marti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarantino
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Francesc
authors.initials: F
authors.lastname: Valldeoriola
authors.forename: Monica
authors.initials: M
authors.lastname: Gagliardi
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.forename: Mario
authors.initials: M
authors.lastname: Ezquerra
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Joaquim
authors.initials: J
authors.lastname: Ferreira
authors.forename: Grazia
authors.initials: G
authors.lastname: Annesi
authors.forename: Stefano
authors.initials: S
authors.lastname: Goldwurm
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tolosa
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Maurizio
authors.initials: M
authors.lastname: Melis
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D009154:Mutation; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors