Objective: To identify families with an increased risk of Parkinson’s disease (PD) and the gene variants associated with such increased disease risk studying large multi-generation pedigrees.

Background: Several monogenic forms of PD and many genetic factors increasing risk for the disease have been identified, but together they account for only ~ 30% of familial, and 3-5% of sporadic PD. Analysis of multi-generation families with an excess of disease has been shown to be a powerful approach to the identification of disease predisposition genes. This approach was previously used in Utah to identify several cancer predisposition genes.

Method: To identify pedigrees with high-risk of PD, we used the Utah Population Database (UPDB), a unique resource linking extensive genealogy information with medical data. The UPDB now includes information in 3 million individuals who are representative of US and Northern European populations and have a low rate of inbreeding. Currently, the UPDB contains over 4,000 PD cases identified from death certificates who also have 3+ generations of genealogy data.

Results: We identified all clusters of related PD cases in the UPDB, and determined which of these clusters represent a significant excess of PD among pedigree members. 2,357 clusters/pedigrees of PD cases were identified, including from 2 to 43 individuals with PD-related death. Of these, 379 pedigrees including from 2 to 37 PD cases were identified as high-risk (p<0.05).  More than 80% of the identified clusters of related PD cases were therefore excluded from further consideration for not having a significant excess of PD among the pedigree members. We then used two existing biorepositories to identify DNA samples from pairs of related cases in each PD pedigree. 182 clusters with genealogy data and 2-7 sampled cases were identified; 25 of the pedigrees had a significant excess of PD cases and at least one pair of related cases. Whole Exome Sequencing and bioinformatics analysis of sequence data in a subset of these samples is currently underway.

Conclusion: From a total of 2,357 PD pedigrees in the Utah population, we have identified 379 with a statistically significant excess of PD-related deaths. From this group, we selected 25 pedigrees with DNA samples from at least one pair of related cases. The identification of gene variants associated with PD risk in these families is currently underway.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-parkinsons-disease-predisposition-genes-in-high-risk-pedigrees/