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Am J Hum Genet. 2018 Dec 6;103(6):874-892. doi: 10.1016/j.ajhg.2018.10.018. Epub 2018 Nov 29.

Parkinson-Associated SNCA Enhancer Variants Revealed by Open Chromatin in Mouse Dopamine Neurons.

Author information

1
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
2
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
3
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL 32224, USA.
4
Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
5
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
7
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; US Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA.
8
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; US Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA.
9
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neuroscience Track, Mayo Graduate School, Jacksonville, FL 32224, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA.
10
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: andy@jhmi.edu.

Abstract

The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD), and modulation of risk by common variants in PD has been well established through genome-wide association studies (GWASs). We acquired open chromatin signatures of purified embryonic mouse MB DA neurons because we anticipated that a fraction of PD-associated genetic variation might mediate the variants' effects within this neuronal population. Correlation with >2,300 putative enhancers assayed in mice revealed enrichment for MB cis-regulatory elements (CREs), and these data were reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directed reporter expression in catecholaminergic neurons from transgenic mice and zebrafish. Sequencing of this CRE in 986 individuals with PD and 992 controls revealed two common variants associated with elevated PD risk. To assess potential mechanisms of action, we screened >16,000 proteins for DNA binding capacity and identified a subset whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identified a single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk variants. Our work posits a model for how common variation at SNCA might modulate PD risk and highlights the value of cell-context-dependent guided searches for functional non-coding variation.

KEYWORDS:

ATAC-seq; Parkinson disease; alpha-synuclein (SNCA); chromatin accessibility; dopaminergic neurons; enhancer; regulatory variation

PMID:
30503521
PMCID:
PMC6288322
DOI:
10.1016/j.ajhg.2018.10.018
[Indexed for MEDLINE]
Free PMC Article

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