Objective:

To identify rare genetic variants associated with increased risk of Parkinson’s disease (PD) in multi-generation, high-risk pedigrees. 

Background:

Monogenic forms and genetic risk factors for PD have been identified, but together they explain only a fraction of familial and sporadic PD. High-risk pedigree studies offer a powerful method for identification of genetic variants affecting predisposition to PD.

Design/Methods:

Previously sampled PD-affected relatives belonging to pedigrees exhibiting a statistically significant excess of PD were whole exome sequenced (WES) to identify rare, shared variants as candidate predisposition variants for PD. We identified pedigrees with high-risk of PD using the Utah Population Database (UPDB), a resource linking extensive genealogy information with medical record and other public health data sources. PD cases were identified by PD listed as a cause of death on death certificates. Sequencing results were compared to association results in the PD DNA Variant Browser.

Results:

We identified 2,357 clusters/pedigrees that included from 2 to 43 sampled individuals with PD-related deaths.  From this group, we selected 379 high-risk clusters with 2-37 PD cases and significant excess of PD among pedigree members (p<0.05). We then selected 25/379 pedigrees with a significant excess of PD cases and at least one pair of related DNA case samples. WES and bioinformatics analysis of a PD-affected cousin pair from each high-risk pedigree identified 242 rare, shared variants in 221 genes.  Of these, 16 genes showed significant association with PD risk in the PD DNA Variant Browser.

Conclusions:

WES in pairs of related sampled PD cases from high-risk pedigrees led to the identification of shared DNA variants in 221 genes, 16 of which were identified in previous studies. Validation studies of some of these candidate PD predisposition variants in these families are currently underway.