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 r2 ≥ 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.
Highlights
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
Most (>90%) of the identified index SNPs in PD GWAS7,8 are located in noncoding DNA regions, making the assignment of potential functionality or causality-even the identification of the specific genes associated with the risk-SNPs-quite challenging
One of the 77 Roadmap Epigenomics Mapping Consortium (REMC) tissues was derived from human substantia nigra, which contains the dopaminergic neurons that undergo extensive degeneration in PD
Summary
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 addition to the rare Mendelian-inherited cases of PD, the genetic predisposition to PD includes at least 26 common single nucleotide polymorphism (SNP) variants (“index SNPs”), each imposing low but significant risk[7,8]. These risk loci associated with PD were discovered by population-based genome-wide association studies (GWAS), published in 2014 in a comprehensive large-scale meta-analysis of reproducible hits[7] and conveniently summarized in a Cell snapshot[3]. They were found respectively in lymphocytes, mesendoderm, brain-, liverand fat cells, allowing refined hypotheses to be formulated for the genetic predisposition to PD at these loci
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