Identifying the Genetic Factors Contributing to Parkinson’s disease
A long-standing effort of our laboratory is to identify the genetic factors contributing to ALS. Over the past year, we have additionally turned our efforts to identifying genetic factors contributing to Parkinson’s disease (PD). In many aspects, ALS and PD are very similar. In both ALS and PD, most cases are considered sporadic, however ~10-20% are familial in nature. Both diseases display high genetic heterogeneity and pathogenic genes in both display incomplete penetrance. However, the two diseases differ in our knowledge of the known genetic factors contributing to familial cases. In FALS, the genetic cause has been identified in approximately two-thirds of cases. In contrast, the genetic cause has only been identified in ~30-40% of familial PD cases.
We have recently applied and developed methods of using RVB analysis to identify novel factors contributing to FALS. This approach has proven to be very successful and has allowed us to identified variants in the TUBA4A gene and a second unpublished gene that contribute to FALS. As such, we have chosen to apply this same approach towards deciphering the genetics of familial PD. Towards this goal, we have established a collaboration with Dr. Tatiana Foroud, a leader in PD genetics, to accomplish this goal. Together, we have recently completed exome sequencing of 1,567 familial PD cases derived from 1,089 PD pedigrees with no known genetic cause. To our best knowledge, this represents the largest dataset of familial PD exomes in existence. We have recently begun the analysis of this data and anticipate obtaining our preliminary results in ~6 months. As with any genetic study, replication in a second cohort is essential to establish the validity of your results. To prepare for this step, we have gained access to two large, independent PD replication cohorts. The first consists of over 800 familial PD cases allowing us to replicate our initial observation. The second consists of over 3,000 sporadic PD to characterize our novel gene discovery to a broader group of PD. Based on this strong dataset, we are confident in identifying novel genetic factors contributing to familial PD. Our access to WGS data from a large control population through our Project MinE effort will further facilitate this study.
Similar to our ALS genetic research, we anticipated that the investigation of PD genetics will continue to be a major focus of my laboratory for the foreseeable future as there are many lines of research that can be pursued. Obviously, the identification of novel familial PD genes opens up several new lines of inquiry to understand the pathogenesis of this disease. This again could lead to the development of new murine models for PD and their subsequent studies. Given the possible overlap of neurodegenerative diseases, we also intend to take advantage of these familial ALS and PD exome cohorts to investigate whether there is a possible genetic overlap. Furthermore, our longer-term plan is to eventually WGS these familial PD samples as we are currently pursuing with our FALS cases. This will again allow us to investigate to contribution of non-coding regions of the genome to familial PD.