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

Abstract

ObjectiveTo discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.MethodsIn 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.ResultsAmong 71 established PD risk variants, we detected multiple suggestive associations with PD motor subtype, including GPNMB (rs199351, psubtype = 0.01, pratio = 0.03), SH3GL2 (rs10756907, psubtype = 0.02, pratio = 0.01), HIP1R (rs10847864, psubtype = 0.02), RIT2 (rs12456492, psubtype = 0.02), and FBRSL1 (rs11610045, psubtype = 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, pratio = 6.6 × 10−7), which harbors an independent risk allele for essential tremor.ConclusionsMultiple 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.

EndophilinA-dependent coupling between activity-dependent calcium influx and synaptic autophagy is disrupted by a Parkinson-risk mutation

“…There are several lines of human genetic evidence that indicate a role for ENDOA1 in the development of PD. There are two independent GWAS signals in the vicinity of the SH3GL2 gene that encodes ENDOA1 (Alfradique-Dunham et al, 2021; Chang et al, 2017; Germer et al, 2019; Nalls et al, 2019). Furthermore, there is a risk-conferring missense mutation in the SH3GL2 gene of PD patients (Germer et al, 2019) that encodes a Glycine to Valine transition at position 276 in the flexible region of ENDOA1.…”

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

“…Two large studies from 2021, confirmed that PD patients with APOE E4 allele or GBA variants are at increased risk of faster cognitive deterioration and identified novel polymorphism linked with faster cognitive (RIMS2, TMEM108, and WWOX) and motor (ATP8B2) progression (Liu et al, 2021;Tan et al, 2021). Another GWAS study in 2021, on 3,212 PD cases, did not find any significant association between common variants and PD motor subtypes (TD/PIGD) (Alfradique-Dunham et al, 2021). However, the authors reported multiple suggestive associations, including the polymorphisms of GPNMB (rs199351), SH3GL2 (rs10756907), HIP1R (rs10847864), RIT2 (rs12456492), FBRSL1 (rs11610045), and STK32B (rs2301857) genes (Alfradique-Dunham et al, 2021).…”

The Big Picture of Neurodegeneration: A Meta Study to Extract the Essential Evidence on Neurodegenerative Diseases in a Network-Based Approach

“…For all NDD but HD, a child term was given, which was also included in the data acquisition step. In total, 153 studies with genomic data were used for the analyses (Maraganore et al, 2005;Fung et al, 2006;Coon et al, 2007;Reiman et al, 2007;Schymick et al, 2007;van Nakamura et al, 2020;Ryu et al, 2020;Alfradique-Dunham et al, 2021;Bone et al, 2021;DeMichele-Sweet et al, 2021;de Rojas et al, 2021;Kang et al, 2021;Loesch et al, 2021;Park et al, 2021;Reddy et al, 2021;Rodrigo and Nyholt, 2021;Sakaue et al, 2021;Schwartzentruber et al, 2021;Shigemizu et al, 2021;Smeland et al, 2021;Tan et al, 2021;Wightman et al, 2021).…”