Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study

Ari Siitonen; Michael A Nalls; Dena Hernández; J Raphael Gibbs; Jinhui Ding; Pauli Ylikotila; Connor Edsall; Andrew Singleton; Kari Majamaa

doi:10.1016/j.neurobiolaging.2017.01.019

Genetics of early-onset Parkinson's disease in Finland: exome sequencing and genome-wide association study

Neurobiol Aging. 2017 May:53:195.e7-195.e10. doi: 10.1016/j.neurobiolaging.2017.01.019. Epub 2017 Feb 2.

Authors

Ari Siitonen¹, Michael A Nalls², Dena Hernández³, J Raphael Gibbs⁴, Jinhui Ding⁴, Pauli Ylikotila⁵, Connor Edsall⁴, Andrew Singleton⁴, Kari Majamaa⁶

Affiliations

¹ 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.
² Laboratory of Neurogenetics, National Institute on Aging, Bethesda, USA; Kelly Services, Rockville, MD, USA.
³ Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
⁴ Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD, USA.
⁵ Division of Clinical Neurosciences, Department of Neurology, Turku University Hospital, Turku, Finland; Department of Neurology, Institute of Clinical Medicine, University of Turku, Turku, Finland.
⁶ 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.

PMID: 28256260
PMCID: PMC5385296
DOI: 10.1016/j.neurobiolaging.2017.01.019

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.

Keywords: Finnish; GWAS; PD; WES; WXS.

MeSH terms

Base Sequence
Cohort Studies
Exome / genetics*
Finland
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study*
Humans
Parkinson Disease / genetics*
Phosphoproteins / genetics
Ribonucleoproteins / genetics
Sequence Analysis, DNA / methods*
alpha 1-Antitrypsin / genetics

Substances

MPHOSPH10 protein, human
Phosphoproteins
Ribonucleoproteins
SERPINA1 protein, human
alpha 1-Antitrypsin

Abstract

MeSH terms

Substances

Grants and funding