Dataset Information

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.

SUBMITTER: Alfradique-Dunham I

PROVIDER: S-EPMC8112852 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Alfradique-Dunham Isabel I Al-Ouran Rami R von Coelln Rainer R Blauwendraat Cornelis C Hill Emily E Luo Lan L Stillwell Amanda A Young Emily E Kaw Anita A Tan Manuela M Liao Calwing C Hernandez Dena D Pihlstrom Lasse L Grosset Donald D Shulman Lisa M LM Liu Zhandong Z Rouleau Guy A GA Nalls Mike M Singleton Andrew B AB Morris Huw H Jankovic Joseph J Shulman Joshua M JM

Neurology. Genetics 20210128 2

<h4>Objective</h4>To discover genetic determinants of Parkinson disease (PD) motor subtypes, including tremor dominant (TD) and postural instability/gait difficulty (PIGD) forms.<h4>Methods</h4>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 regre ...[more]

PMID: 33987465

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Project description:Background and objectivesConsiderable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations.MethodsA meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC).ResultsThe COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10-8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10-9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10-8).DiscussionOur study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.

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Dataset Information

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

Objective

Methods

Results

Conclusions

Publications

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

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