title: Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study.
abstract: Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been found. Here, we carried out whole-exome sequencing (WES) on 438 Finnish patients with early-onset PD. We also reanalyzed previous data from genome-wide association studies (GWAS) on the same cohort. Variants in the CEL gene/locus were associated with PD in both GWAS and WES analysis. Exome-wide gene-based association tests also identified the MPHOSPH10, TAS2R19, and SERPINA1 genes in the discovery data set (p < 2.5E-6). MPHOSPH10 had estimated odds ratio (OR) of 1.53, and the rs141620200 variant in SERPINA1 had OR of 1.27. We identified several candidate genes, but further investigation is required to determine the role of these genes in PD.
authors.affiliation: Research Unit of Clinical Neuroscience, Department of Neurology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Department of Neurology, Oulu University Hospital and University of Oulu, Oulu, Finland. Electronic address: ari.siitonen@iki.fi.
authors.forename: Ari
authors.initials: A
authors.lastname: Siitonen
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA; Kelly Services, Rockville, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
authors.forename: Dena
authors.initials: D
authors.lastname: Hernández
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Division of Clinical Neurosciences, Department of Neurology, Turku University Hospital, Turku, Finland; Department of Neurology, Institute of Clinical Medicine, University of Turku, Turku, Finland.
authors.forename: Pauli
authors.initials: P
authors.lastname: Ylikotila
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Connor
authors.initials: C
authors.lastname: Edsall
authors.affiliation: Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.affiliation: Research Unit of Clinical Neuroscience, Department of Neurology, University of Oulu, Oulu, Finland; Medical Research Center Oulu, Department of Neurology, Oulu University Hospital and University of Oulu, Oulu, Finland; Department of Neurology, Oulu University Hospital, Oulu, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Majamaa
mesh_terms: D001483:Base Sequence; D015331:Cohort Studies; D059472:Exome / Q000235:genetics*; D005387:Finland; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D000515:alpha 1-Antitrypsin / Q000235:genetics
chemical_list: C111101:MPHOSPH10 protein, human; D010750:Phosphoproteins; D012261:Ribonucleoproteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: Finnish; GWAS; PD; WES; WXS