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

Isabel Alfradique-Dunham; Rami Al-Ouran; Rainer von Coelln; Cornelis Blauwendraat; Emily Hill; Lan Luo; Amanda Stillwell; Emily Young; Anita Kaw; Manuela Tan; Calwing Liao; Dena Hernandez; Lasse Pihlstrom; Donald Grosset; Lisa M Shulman; Zhandong Liu; Guy A Rouleau; Mike Nalls; Andrew B Singleton; Huw Morris; Joseph Jankovic; Joshua M Shulman

doi:10.1212/NXG.0000000000000557

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

Neurol Genet. 2021 Jan 28;7(2):e557. doi: 10.1212/NXG.0000000000000557. eCollection 2021 Apr.

Authors

Isabel Alfradique-Dunham¹, Rami Al-Ouran¹, Rainer von Coelln¹, Cornelis Blauwendraat¹, Emily Hill¹, Lan Luo¹, Amanda Stillwell¹, Emily Young¹, Anita Kaw¹, Manuela Tan¹, Calwing Liao¹, Dena Hernandez¹, Lasse Pihlstrom¹, Donald Grosset¹, Lisa M Shulman¹, Zhandong Liu¹, Guy A Rouleau¹, Mike Nalls¹, Andrew B Singleton¹, Huw Morris¹, Joseph Jankovic¹, Joshua M Shulman¹

Affiliation

¹ Department of Neurology (I.A.-D., E.H., L.L., A.S., E.Y., A.K., J.J., J.M.S.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (R.A.-O., Z.L.), Baylor College of Medicine, Houston, TX; Jan and Dan Duncan Neurological Research Institute (R.A.-O., Z.L., J.M.S.), Texas Childrens Hospital, Houston, TX; Department of Neurology (R.C., L.M.S.), University of Maryland School of Medicine, Baltimore, MD; Molecular Genetics Section (C.B., D.H., M.N., A.B.S.), Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD; Department of Clinical and Movement Neurosciences (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre (M.T., H.M.), UCL Queen Square Institute of Neurology, University College London, London, UK; Montreal Neurological Institute (C.L., G.A.R.), Montréal, Quebec, Canada; Department of Human Genetics (C.L., G.A.R.), McGill University, Montréal, Quebec, Canada; Department of Neurology (L.P.), Oslo University Hospital, Oslo, Norway; Department of Neurology (D.G.), Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK; Department of Neurology and Neurosurgery (G.A.R.), McGill University, Montréal, Quebec, Canada; Data Tecnica International (M.N.), Glen Echo, MD; Parkinsons Disease Center and Movement Disorders Clinic (J.J., J.M.S.), Department of Neurology, Baylor College of Medicine, Houston, TX; Department of Molecular & Human Genetics (J.M.S.), Baylor College of Medicine, Houston, TX; and Department of Neuroscience (J.M.S.), Baylor College of Medicine, Houston, TX.

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.

Abstract

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