Abstract Details

Title Identification of candidate Parkinson’s disease predisposition genes in high-risk pedigrees

Topic Movement Disorders

Presentation(s) S42 - Movement Disorders: Genetics and Risk Modifiers (3:30 PM-3:42 PM)

Poster/Presentation
Number 001

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.

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

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.

Authors/Disclosures
Paolo M. Moretti, MD (University of Utah) PRESENTER	The institution of Dr. Moretti has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie, Inc. The institution of an immediate family member of Dr. Moretti has received research support from NIH. The institution of an immediate family member of Dr. Moretti has received research support from VHA. The institution of an immediate family member of Dr. Moretti has received research support from DOD.
Karla P. Figueroa (University of Utah)	Ms. Figueroa has nothing to disclose.
Stefan M. Pulst, MD, FAAN (University of Utah)	Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care.
Alessandro Dotti	Mr. Dotti has nothing to disclose.
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