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

Background: Our current knowledge of PD genetics derives from two main approaches: the analysis of nuclear families carrying rare highly penetrant alleles, and GWAS. Using these methods, monogenic and polygenic PD risk factors have been identified, and together they account for 5-10% of familial and sporadic PD. It is estimated that an additional 20-25% of PD cases have a significant inherited component. We propose that studying high-risk, multi-generational pedigrees offers a powerful additional method for the identification of genetic variants affecting predisposition to PD.

Method: 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. These pedigrees showed a statistically significant excess (p<0.05) of PD compared to the Utah population. Cases were identified by PD listed as a cause of death on death certificates. We performed whole exome sequencing (WES) on 16 PD cousin pairs and identified all rare (MAF<0.005), shared variants to identify candidate predisposition variants.  For validation we considered evidence for significant association with PD risk in Genebass, a resource of WES-based association statistics for a variety of phenotypes using UK Biobank data.

Results: We identified 278 pedigrees that included 2-10 sampled individuals with PD-related deaths.  From this group, we selected 28 high-risk clusters with significant excess of PD among pedigree members (p<0.05). We then selected the 16 pedigrees that also included one pair of first cousins with available DNA. WES and bioinformatics analysis of these PD-affected cousin pairs identified 242 rare, shared variants in 221 genes.  Of these, 4 variants in 4 unique genes (SLIT1, FOXD2, ADAMTSL5, and PRSS3) showed significant (p<0.05) association with PD risk in UK Biobank data.

Conclusion: WES in pairs of related sampled PD cases from high-risk multi-generational pedigrees led to the identification of shared DNA variants in 221 genes, 4 of which are found significant in UK Biobank data. Additional segregation studies of some of these candidate PD predisposition variants in these families are currently underway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/using-multi-generational-high-risk-pedigrees-to-identify-candidate-parkinsons-disease-predisposition-genes/