Polymorphisms in candidate genes in the ubiquitin-proteasome system and Parkinson's disease: A case-control genetic association study controlling for population structure.

摘要

Parkinson's disease (PD) is a complex disorder, resulting from both genetic and environmental factors. Several genes have been associated with monogenic forms of PD. Functional characterization of these genes has highlighted the importance of a number of pathways, including the ubiquitin-proteasome system (UPS), in PD pathogenesis. The first chapter of this dissertation reviews PD genetics, summarizes evidence supporting a role for the UPS in PD etiology, and provides background on two UPS candidate genes: UCHL1 and USP24. The second chapter presents results from a case control study of 249 cases and 248 age and gender matched controls. We did not observe evidence for an association between variation in either UCHL1 or USP24 and PD. Stratified analysis found marginal evidence for an association between SNP rs930758 (a SNP in high LD with the UCHL1 S18Y variant) and decreased risk in PD in early onset cases (OR=0.45, 95% CI: 022-0.91). This result was not statistically significant after adjustment for multiple testing; however, a similar trend was observed in a replication sample of 303 cases and 395 controls. The second half of this dissertation focuses on population structure and population stratification in European Americans. Chapter 3 presents a critical evaluation of current methods used to evaluate population structure and stratification and chapter 4 applies these methods to our case-control sample. We observed evidence for intercontinental population structure, with two individuals showing genetic evidence for non-European ancestry. When we restricted our analysis to 495 subjects not showing evidence of intercontinental structure, we found only minor evidence for genetic structure. This observed structure did not cluster individuals, was identical for our case and control samples, and did not correlate with self-reported ancestry. Applying methods to adjust for population structure did not substantively alter the results of tests of association for four PD candidate genes.