title: Epigenome-wide DNA methylation analysis in siblings and monozygotic twins discordant for sporadic Parkinson's disease revealed different epigenetic patterns in peripheral blood mononuclear cells.
abstract: Numerous studies have elucidated the genetics of Parkinson's disease; however, the aetiology of the majority of sporadic cases has not yet been resolved. We hypothesized that epigenetic variations could be associated with PD and evaluated the DNA methylation pattern in PD patients compared to brothers or twins without PD. The methylation of DNA from peripheral blood mononuclear cells of 62 discordant siblings including 24 monozygotic twins was characterized with Illumina DNA Methylation 450K bead arrays and subsequently validated in two independent cohorts: 221 PD vs. 227 healthy individuals (cohort 1) applying Illumina's VeraCode and 472 PD patients vs. 487 controls (cohort 2) using pyrosequencing. We choose a delta beta of >15 % and selected 62 differentially methylated CpGs in 51 genes from the discordant siblings. Among them, three displayed multiple CpGs per gene: microRNA 886 (MIR886, 10 CpGs), phosphodiesterase 4D (PDE4D, 2 CpGs) and tripartite motif-containing 34 (TRIM34, 2 CpGs). PDE4D was confirmed in both cohorts (p value 2.44e-05). In addition, for biomarker construction, we used the penalized logistic regression model, resulting in a signature of eight CpGs with an AUC of 0.77. Our findings suggest that a distinct level of PD susceptibility stems from individual, epigenetic modifications of specific genes. We identified a signature of CpGs in blood cells that could separate control from disease with a reasonable discriminatory power, holding promise for future epigenetically based biomarker development.
authors.affiliation: Department of Neurology, University of Bonn, 53105, Bonn, Germany. oliver.kaut@ukb.uni-bonn.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kaut
authors.affiliation: Department of Neurology, University of Bonn, 53105, Bonn, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.affiliation: Laboratory for Epigenetics and Environment (LEE), Centre National de Génotypage, CEA-Institut de Génomique, 91057, Evry Cedex, France.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Laboratory for Epigenetics and Environment (LEE), Centre National de Génotypage, CEA-Institut de Génomique, 91057, Evry Cedex, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Busato
authors.affiliation: Laboratory for Epigenetics and Environment (LEE), Centre National de Génotypage, CEA-Institut de Génomique, 91057, Evry Cedex, France.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute for Human Genetics, Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hofmann
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159, Mannheim, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Bonn-Aachen International Center for IT (B-IT), Algorithmic Bioinformatics, University of Bonn, 53113, Bonn, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.affiliation: Department of Neurology, University of Bonn, 53105, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany.
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D010300:Parkinson Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D014430:Twins, Monozygotic / Q000235:genetics*
keywords: Biomarker; Microarray; Movement disorder; Neurodegeneration