Parkinson-associatedSNCAenhancer variants revealed by open chromatin in mouse dopamine neurons

Abstract

30The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of 31Parkinson disease (PD) and modulation of risk by common variation in PD has been well established 32 through GWAS. Anticipating that a fraction of PD-associated genetic variation mediates their effects 33 within this neuronal population, we acquired open chromatin signatures of purified embryonic mouse 34 MB DA neurons. Correlation with >2,300 putative enhancers assayed in mice reveals enrichment for MB 35 cis-regulatory elements (CRE), data reinforced by transgenic analyses of six additional sequences in 36 zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directs reporter expression in 37 catecholaminergic neurons of transgenic mice and zebrafish. Sequencing of this CRE in 986 PD patients 38 and 992 controls reveals two common variants associated with elevated PD risk. To assess potential 39 mechanisms of action, we screened >20,000 DNA interacting proteins and identify a subset whose 40 binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identifies a 41 single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk 42 variants. Our work posits a model for how common variation at SNCA may modulate PD risk and 43 highlights the value of cell context-dependent guided searches for functional non-coding variation.