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Series GSE122450 Query DataSets for GSE122450
Status Public on Nov 14, 2018
Title Parkinson-associated SNCA enhancer variants revealed by open chromatin in mouse dopamine neurons
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Summary The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD) and modulation of risk by common variation in PD has been well established through GWAS. Anticipating that a fraction of PD-associated genetic variation mediates their effects within this neuronal population, we acquired open chromatin signatures of purified embryonic mouse MB DA neurons. Correlation with >2,300 putative enhancers assayed in mice reveals enrichment for MB cis-regulatory elements (CRE), data reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directs reporter expression in catecholaminergic neurons of transgenic mice and zebrafish. Sequencing of this CRE in 986 PD patients and 992 controls reveals two common variants associated with elevated PD risk. To assess potential mechanisms of action, we identify proteins whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identifies 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 may modulate PD risk and highlights the value of cell context-dependent guided searches for functional non-coding variation.
Overall design 6 ATAC-seq libraries and 8 RNA-seq samples from sorted mouse Th-EGFP dopaminergic neurons collected at E15.5 from two distinct brain regions (midbrain and forebrain)
Contributor(s) McClymont SA, Hook PW, Soto AI, Reed X, Law WD, Kerans SJ, Waite EL, Briceno NJ, Thole JF, Heckman MG, Diehl NN, Wszolek ZK, Moore CD, Zhu H, Akiyama JA, Dickel DE, Visel A, Pennacchio LA, Ross OA, Beer MA, McCallion AS
Citation(s) 30503521, 36747739, 36824793
Submission date Nov 13, 2018
Last update date Mar 09, 2023
Contact name Andy McCallion
Organization name Johns Hopkins School of Medicine
Department Institute of Genetic Medicine
Street address 733 N Broadway, MRB 446
City Baltimore
State/province MD
ZIP/Postal code 21205
Country USA
Platforms (2)
GPL16417 Illumina MiSeq (Mus musculus)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
Samples (15)
GSM3466715 MB_ATAC_rep1
GSM3466716 MB_ATAC_rep2
GSM3466717 MB_ATAC_rep2 (DeepSeq)
BioProject PRJNA505267
SRA SRP168416

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE122450_RAW.tar 10.3 Mb (http)(custom) TAR (of TXT)
GSE122450_gencode.vM9_rpkm.txt.gz 2.1 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record
Processed data provided as supplementary file

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