Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes

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 × 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.