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

Abstract

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.

Figure 1. PD Genetic Risk Score Associates With Tremor/Postural Instability/Gait Difficulty Score Ratio

Error bars represent 95% confidence intervals. The size of the black squares represents the effect size from each cohort. The combined estimate for all cohorts is represented by the red diamond with the width of the diamond representing the 95% confidence interval bounds. The summary effect = −0.0389 (p = 0.0156). PD = Parkinson disease.

Figure 2. STK32B Locus Association With PD Subtype Ratio

Locus zoom plot highlighting the association signal at the STK32B locus. The top variant associated with PD subtype ratio, rs2301857, is highlighted along with other variants in linkage disequilibrium. Another variant in the same gene, rs10937625 (dashed line), has been reported as significantly associated with essential tremor (ET), but is not associated with PD subtype ratio. The 2 variants appear independent and do not show substantial linkage disequilibrium (R2 = 0.002, D' = 0.184). PD = Parkinson disease