Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes
Isabel Alfradique‐Dunham, Rami Al‐Ouran, Rainer von Coelln, Cornelis Blauwendraat, Emily J. Hill, Lan Luo, Amanda Stillwell, Emily Young, Anita Kaw, Manuela Tan, Calwing Liao, Dena Hernández, Lasse Pihlstrøm, Donald G. Grosset, Lisa M. Shulman, Zhandong Liu, Guy A. Rouleau, Mike A. Nalls, Andrew Singleton, Huw R. Morris, Joseph Jankovic, Joshua Shulman
Abstract
<h3>Objective</h3> To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms. <h3>Methods</h3> 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 Parkinson9s 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. <h3>Results</h3> Among 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including <i>GPNMB</i> (<i>rs199351</i>, <i>p</i><sub>subtype</sub> = 0.01, <i>p</i><sub>ratio</sub> = 0.03), <i>SH3GL2</i> (<i>rs10756907</i>, <i>p</i><sub>subtype</sub> = 0.02, <i>p</i><sub>ratio</sub> = 0.01), <i>HIP1R</i> (<i>rs10847864</i>, <i>p</i><sub>subtype</sub> = 0.02), <i>RIT2</i> (<i>rs12456492</i>, <i>p</i><sub>subtype</sub> = 0.02), and <i>FBRSL1</i> (<i>rs11610045</i>, <i>p</i><sub>subtype</sub> = 0.02). A PD genetic risk score integrating all 71 PD risk variants was also associated with subtype ratio (<i>p</i> = 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 <i>STK32B</i> locus (rs2301857, <i>p</i><sub>ratio</sub> = 6.6 × 10<sup>−7</sup>), which harbors an independent risk allele for essential tremor. <h3>Conclusions</h3> Multiple PD risk alleles may also modify clinical manifestations to influence PD motor subtype. The discovery of a novel variant at <i>STK32B</i> suggests a possible overlap between genetic risk for essential tremor and tremor-dominant PD.