title: Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson's disease etiology.
abstract: Recent genome-wide association studies (GWAS) of Parkinson's disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r(2) ≥ 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (-logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development.
authors.affiliation: Bioinformatics and Computational Biology Research Center, Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Coetzee
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Brundin
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Brundin
authors.affiliation: Bioinformatics and Computational Biology Research Center, Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hazelett
authors.affiliation: Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Coetzee
mesh_terms: D002877:Chromosomes, Human; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D010300:Parkinson Disease / Q000209:etiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors