Abstract Details

Title Genome-Wide Association Study Meta-Analysis For Parkinson Disease Motor Subtypes

Topic Movement Disorders

Presentation(s) S53 - Movement Disorders: Genetics and Clinical Features (4:14 PM-4:25 PM)

Poster/Presentation
Number 005

Background

PD is clinically heterogeneous, and at least two major motor subtypes are recognized, including tremor dominant (TD) and postural instability gait difficulty (PIGD) forms (Jankovic 1990; Stebbins 2013). Rare variants in LRRK2 and GBA have been associated with characteristic motor and non-motor profiles. More common genetic variants, including many other established PD susceptibility alleles, have yet to be systematically evaluated for impact on PD subtypes.

Objective

To discover genetic modifiers of Parkinson disease (PD) motor subtypes.

Design/Methods Genome-wide association study (GWAS) meta-analysis was performed in 8 cohorts including 3,212 PD cases of European ancestry (65% male, mean age: 64 years at evaluation, avg. disease duration: 5 years). We examined 2 complementary outcome traits based on the UPDRS or MDS-UPDRS, including (1) the dichotomous TD vs. PIGD subtype or (2) a continuous TD/PIGD ratio. Following quality control and imputation, ~5 million variants remained for analysis. For each study, regression was implemented, adjusting for onset age, gender, disease duration, and 5 ancestry principal components, followed by meta-analysis.

Results

PD motor subtypes in our cohort included 47% TD, 41% PIGD, and 12% indeterminate. Among 44 established PD-risk variants (Chang et al. 2017), we detected nominal associations with motor subtype at TMEM163 (rs6430538, p_ratio=8.7x10^-4, p_subtype=0.01), GPNMB (rs199347, p_subtype=0.01, p_ratio=0.04), SYT4 (rs12456492, p_subtype =0.02), and DLG2 (rs3793947, p_subtype=0.045). A genetic risk score including all PD risk alleles was also associated with subtype (p_ratio=0.04). Although no variants (freq. > 0.01) reached genome-wide significance, our top result, rs2301857 (p_ratio=6.6x10^-7) falls within the STK32B locus, adjacent to a risk allele for essential tremor (Müller 2016).

Conclusions

Several PD risk loci also modify PD motor subtypes. Although increased sample sizes are needed to resolve remaining uncertainties, the discovery of a suggestive association at STK32B hints at potential overlap between risk for essential tremor and the tremor-dominant PD motor subtype.

Authors/Disclosures
Isabel Alfradique-Dunham, MD (Washington University in St. Louis) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Emily J. Hill, MD (University of Cincinnati)	Dr. Hill has nothing to disclose.
Lan Luo, MD, MS (Beth Israel Deaconess Medical Center)	Dr. Luo has received personal compensation in the range of $0-$499 for serving as a Consultant for Destum Partners. Dr. Luo has received personal compensation in the range of $0-$499 for serving as a Consultant for Guidepoint Global. Dr. Luo has received research support from BIDMC/HMS.
	No disclosure on file
	No disclosure on file
Zhandong Liu	Zhandong Liu has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
J.J. Van Hilten (Duphar Nederland BV)	No disclosure on file
	No disclosure on file
Lisa M. Shulman, MD, FAAN (University of Maryland School of Medicine)	The institution of Dr. Shulman has received research support from NIH. Dr. Shulman has received publishing royalties from a publication relating to health care. Dr. Shulman has received publishing royalties from a publication relating to health care.
Joseph Jankovic, MD, FAAN (Baylor College of Medicine)	Dr. Jankovic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Revance. Dr. Jankovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Revance, Allergan. The institution of Dr. Jankovic has received research support from Baylor College of Medicine. Dr. Jankovic has received research support from Abbvie. The institution of Dr. Jankovic has received research support from Abbvie.
	No disclosure on file
Andrew Singleton	An immediate family member of Andrew Singleton has received personal compensation for serving as an employee of GeneDx. Andrew Singleton has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Nature Partner Journals Parkinson Disease. Andrew Singleton has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders Journal. An immediate family member of Andrew Singleton has stock in GeneDx. The institution of Andrew Singleton has received research support from Michael J Fox Foundation. Andrew Singleton has received intellectual property interests from a discovery or technology relating to health care. Andrew Singleton has received intellectual property interests from a discovery or technology relating to health care.
Huw R. Morris, MD, PhD	Dr. Morris has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Morris has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aprinoia. Dr. Morris has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Morris has received personal compensation in the range of $50,000-$99,999 for serving as an Expert Witness for Personal injury / Negligence cases. The institution of Dr. Morris has received research support from Parkinson's UK. The institution of Dr. Morris has received research support from Michael J Fox Foundartion. The institution of Dr. Morris has received research support from Cure Parkinson's Trust. The institution of Dr. Morris has received research support from PSP Association. The institution of Dr. Morris has received research support from CBD Solutions. The institution of Dr. Morris has received research support from Drake Foundation. The institution of Dr. Morris has received research support from Medical Research Council. Dr. Morris has received intellectual property interests from a discovery or technology relating to health care. Dr. Morris has a non-compensated relationship as a Scientific Advisory Board with Cure PSP that is relevant to AAN interests or activities. Dr. Morris has a non-compensated relationship as a Scientific Advisory Board with Parkinson's UK that is relevant to AAN interests or activities.
Joshua M. Shulman, MD, PhD, FAAN (Duncan Neurological Research Institute)	Dr. Shulman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Helis Medical Foudation. The institution of Dr. Shulman has received research support from National Institutes of Health.

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