Abstract Details

Title Whole Exome Sequencing Analysis of Common Rare Variants in Parkinson and ALS

Topic Movement Disorders

Presentation(s) IN2 - (-)

Poster/Presentation
Number 008

Objective

Background Genetic variants in three genes (ANG (angiogenin), VPS35 and C9ORF72) have been implicated to increase the risk for developing ALS and PD. WES allows the entire exome to be examined at once in multiple genes. Thus whole groups and famiies of genes can be screened for rare changes in the genome.

Design/Methods 219 PD cases and 85 controls were included in the initial analysis. Rare variants (RVs, <5% in the population) in 10 genes were identified in the WES (including indels) and then Sanger sequenced for confirmation. Statistical analysis was performed to see if RVs were more frequent in PD versus controls. Two programs were utilized, RVASSOC and SKAT, which weight RVs differently. Specific variants were not frequent enough to warrant individual statistical analysis.

Results Two genes, FIG4 and ALS2 had significant clustering on analysis. FIG4 had significantly more functional variants in PD versus controls using both RVASSOC and SKAT (p=0.03, 0.02 respectively). ALS2 had more deleterious very rare RVs (Polyphen2) than controls (SKAT, p=0.03), with a trend in RVASSOC (p=0.08). Several specific RVs were only found in PD, and segregated in multiplex families. Interestingly, several specific RVs that were identified have been reported to lead to Spastic Paraplegia as well as ALS.

Conclusions FIG4 interacts in a complex that regulates biosynthesis of PI9(3,5)P2 signaling lipid. FIG4 null mice develop neurodegeneration. Interestingly,FIG4 compound heterozygotes with partial enzyme activity cause Charcot-Marie-Tooth 4J and have been suggested to contribute to ALS as well. Mutations in ALS2 lead to juvenile ALS. Additional data is needed to confirm if these genes have a wider role in the common forms of neurodegeneration.

Authors/Disclosures
Jeffery Vance, MD, PhD (University of Miami) PRESENTER	Dr. Vance has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for neurology genetics.
Karen Nuytemans, PhD (U of Miami, John P. Hussman Institute)	The institution of Dr. Nuytemans has received research support from NIH. The institution of Dr. Nuytemans has received research support from NIH. The institution of Dr. Nuytemans has received research support from Department of Defense. The institution of Dr. Nuytemans has received research support from Margaret Q. Landenberger Foundation. The institution of Dr. Nuytemans has received research support from American Parkinson Disease Association. The institution of Dr. Nuytemans has received research support from Florida Department of Health.
	No disclosure on file
Gary W. Beecham, PhD (University of Miami, Hussman Institute for Human Genomics)	The institution of Dr. Beecham has received research support from NIH. The institution of an immediate family member of Dr. Beecham has received research support from NIH.
	No disclosure on file
	No disclosure on file
	No disclosure on file
William K. Scott, MD (Univ of Miami Miller School of Medicine)	No disclosure on file
Emmanuelle Waubant, MD, PhD, FAAN (USCF MS Center)	The institution of Dr. Waubant has received research support from NIH. The institution of Dr. Waubant has received research support from NMSS. The institution of Dr. Waubant has received research support from PCORI. The institution of Dr. Waubant has received research support from Race to Erase MS. The institution of Dr. Waubant has received research support from Roche. The institution of Dr. Waubant has received research support from Department of Defense. Dr. Waubant has received publishing royalties from a publication relating to health care.

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