Abstract
OBJECTIVE:To determine whether the combination of exome variants in pre-defined functional pathways provides evidence for association with Parkinson disease (PD) risk
BACKGROUND:Previously, we reported association of several biological pathways (KEGG) with PD risk using GWAS data (based on common, often intergenic or intronic, genomic variants with low risk effects). In contrast, exome variants are enriched for ‘rare risk variants’; these are variants with a low frequency but possible higher risk effect on disease. On average, ~85% of exome variants have a frequency <5%, while ~73% are very rare
DESIGN/METHODS:We performed whole exome sequencing in 315 PD patients and 252 controls. Association of sets of variants in pathways/gene groups with PD risk was assessed using the Cochran-Armitage sum/max tests implemented in the RVASSOC program and the Sequence Kernel Association test. Analyzed pathways included 13 top KEGG pathways identified in the previously reported pathway study as well as candidate gene groups ‘mitochondrial’ (MitoCarta) and ‘lysosomal’ genes (Human Lysosome Gene Database), bases on known PD genes functionality. Permutation tests (N=500) on random sets of same-size gene or variant groups were performed to address multiple testing.
RESULTS:When including all identified exome variants, we observed no evidence for association for any of the two gene groups or the 13 tested KEGG pathways after permutation tests. However, in the analyses filtered on freuency we observed significant association in the ‘lysosomal’ gene group for both rare variant analyses (<5% and <1%; p<0.001)
CONCLUSIONS:Our results indicate that common GWAS variants and rare exome variants tend to aggregate in different functional pathways. In addition, rare variants possibly obstructing normal lysosomal function are significantly contributing to PD. Additional analyses are ongoing to elucidate the observed lysosomal signal in this analysis.
Study Supported by:NIND> Disclosure: Dr. Vance has received personal compensation for activities with Covance. Dr. Vance has received royalty payments from Athena Diagnostics. Dr. Vance has received research support from the National Institutes of Health. Dr. Nuytemans has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Inchausti has nothing to disclose. Dr. Maldonado has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Perry has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Pericak-Vance has received personal compensation for activities with the University of Alaska. Dr. Scott has nothing to disclose.