Objective: Confirm the PARK10 locus as a major GWAS locus in autopsy-confirmed (AC) PD and AC controls and identify potential noncoding variants driving the association. 

Background: We previously showed that the PARK10 locus is strongly associated with PD using AC cases and controls (Beecham et al, 2015), but is not associated in clinically-diagnosed datasets. This supports the multiple studies reporting that ~ 20% of clinically diagnosed PD have neuropathological findings other than Lewy body PD.

Methods: DNA of 137 AC cases and 55 AC controls was obtained from the UK Parkinson Disease brain bank.  These were genotyped for rs10788972, the SNP previously described to demonstrate the strongest association. This dataset was analyzed individually and jointly with the previous dataset collected by the Autopsy-confirmed PD Genetics Consortium (Beecham et al. 2015) for genetic association). Variants in the associated region were annotated using the GTEx, RoadMap Epigenome Project and ENCODE data currently available.

Results: Association results from the UK brain bank samples demonstrated significant association for rs10788972 (p=0.02). Joint analysis (621 cases, 1100 controls) demonstrated genome-wide association (p=4.4×10^-9) for the rs10788972 locus. Sequencing data suggest no coding variants are contributing to the signal. We obtained evidence for many noncoding variants located the associated region in expression quantitive trait loci (N=113), regulatory elements (enhancer, promoter, transcription start site; N=47) and transcription factor (TF) binding sites (experimentally defined N=29, in-silico N=173). We identified 24 variants with evidence in all three categories (e.g. rs914722, rs1537323).

Conclusions: These findings confirm PARK10 as a major locus for Lewy body PD, now supported by genome-wide association and previous linkage studies.  We hypothesize that heterogeneity in PD cases AND controls is contributing to the lack of signal when using clinically defined cases and controls. Our data suggest the PARK10 signal is mediated by noncoding variation. Though we identified multiple variants of interest, current noncoding mapping data is limited for PD regions in ENCODE and RoadMap Projects. Additional studies are ongoing to evaluate overall and variant specific functional potential in the PARK10 region in PD brain.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-noncoding-variants-driving-genome-wide-association-of-the-park10-locus-in-autopsy-proven-parkinson-disease-and-controls/