Journal
NEUROLOGY-GENETICS
Volume 7, Issue 2, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/NXG.0000000000000557
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Funding
- Intramural research Program of the NIH, National Institute on Aging
- Parkinsons UK [J-1101, G-1107, H-1703]
- Medical Research Council [G1100643]
- Canadian Institutes of Health Foundation Grant
- Vanier Graduate Scholarship
- Parkinsons UK
- UK National Institute for Health Research
- Glasgow University
- Huffington Foundation
- McGee Foundation
- Jan and Dan Duncan Neurological Research Institute at Texas Childrens Hospital
- Career Award for Medical Scientists from the Burroughs Wellcome Fund
- International PD Genomics Consortium
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The study identified multiple PD risk alleles that may modify clinical manifestations and influence PD motor subtypes. The discovery of a novel variant at the STK32B locus suggests a potential overlap between genetic risk for essential tremor and tremor-dominant PD.
Objective To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms. Methods In 3,212 PD cases of European ancestry, we performed a genome-wide association study (GWAS) examining 2 complementary outcome traits derived from the Unified Parkinson's Disease Rating Scale, including dichotomous motor subtype (TD vs PIGD) or a continuous tremor/PIGD score ratio. Logistic or linear regression models were adjusted for sex, age at onset, disease duration, and 5 ancestry principal components, followed by meta-analysis. Results Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, p(subtype) = 0.01, p(ratio) = 0.03), SH3GL2 (rs10756907, p(subtype) = 0.02, p(ratio) = 0.01), HIP1R (rs10847864, p(subtype) = 0.02), RIT2 (rs12456492, p(subtype) = 0.02), and FBRSL1 (rs11610045, p(subtype) = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (p = 0.026, ss = -0.04, 95% confidence interval = -0.07-0). Based on top results of our GWAS, we identify a novel suggestive association at the STK32B locus (rs2301857, p(ratio) = 6.6 x 10(-7)), which harbors an independent risk allele for essential tremor. Conclusions Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at STK32B suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.
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