Abstract
Objective: To obtain genome-wide significance for the PARK10 locus for autopsy-confirmed Lewy body (LB) Parkinson disease (PD). Background: Previous autopsy studies have found that up to 20% of clinically-diagnosed PD have other/additional neuropathology other than LB-PD on autopsy. This suggests that genetic and pathologic heterogeneity exists that could reduce the power of association analysis in clinical PD. The autopsy confirmed PD genetic consortium (APDGC) was formed, and we recently reported a strong association with PD risk with the previously described PARK10 locus using both autopsy-confirmed (AC)-Lewy body (LB)-PD and AC-controls (Beecham et al, 2015). However, as much larger studies using only clinically-defined cases and controls, have not seen this association, some authors have questioned the validity of the findings of Beecham et al. Design/Methods: DNA on 137 AC-PD cases and 55 AC-controls was obtained from the Parkinson’s UK brain bank. These were genotyped for rs10788972, the SNP demonstrating the strongest previous association. This dataset was analyzed individually for association and then jointly with the previous dataset collected by the Autopsy-confirmed PD Genetics Consortium (APDGC) (Beecham et al, 2015). Results: Using the Parkinson’s UK brain bank samples we demonstrated positive association for rs10788972, with p=0.02. Joint analysis (621 cases, 1200 controls) demonstrated genome-wide association (p = 4.43E-09) with rs10788972. Conclusions: This finding has several important implications for studies in both PD and neurodegeneration. First this confirms PARK10 as a major locus for idiopathic, Lewy-body PD. Second, the reason for the absence of genetic association with PARK10 in clinically-defined cases and controls is unclear. While the most likely mechanism is neuropathic and genetic heterogeneity, it would seem that heterogeneity in BOTH PD cases as well as controls are contributing to this finding. This raises the question whether using clinically identified controls is adding more genetic heterogeneity to current genetic analyses in neurodegenerative studies than previously thought. Study Supported by: NIH/NINDS grant P50NS0171674 (J.Vance P.I.) Disclosure: Dr. Vance has received personal compensation in an editorial capacity for Neurology Genetics. Dr. Vance9s institution has received royalty payments from Athena Diagnostics. Dr. Nuytemans has nothing to disclose. Dr. Gomez has nothing to disclose. Dr. Scott has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Gveric has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Consortium has nothing to disclose.