TY - JOUR
T1 - Genome-Wide Association Study Meta-Analysis for Parkinson Disease Motor Subtypes
AU - Alfradique-Dunham, Isabel
AU - Al-Ouran, Rami
AU - Von Coelln, Rainer
AU - Blauwendraat, Cornelis
AU - Hill, Emily
AU - Luo, Lan
AU - Stillwell, Amanda
AU - Young, Emily
AU - Kaw, Anita
AU - Tan, Manuela
AU - Liao, Calwing
AU - Hernandez, Dena
AU - Pihlstrom, Lasse
AU - Grosset, Donald
AU - Shulman, Lisa M.
AU - Liu, Zhandong
AU - Rouleau, Guy A.
AU - Nalls, Mike
AU - Singleton, Andrew B.
AU - Morris, Huw
AU - Jankovic, Joseph
AU - Shulman, Joshua M.
N1 - Publisher Copyright:
© American Academy of Neurology.
PY - 2021/4/28
Y1 - 2021/4/28
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85116732513
U2 - 10.1212/NXG.0000000000000557
DO - 10.1212/NXG.0000000000000557
M3 - Article
AN - SCOPUS:85116732513
SN - 2376-7839
VL - 7
SP - e557
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 2
ER -