Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype

Christine A. Cooper, Nimansha Jain, Michael D. Gallagher, Daniel Weintraub, Sharon X. Xie, Yosef Berlyand, Alberto J. Espay, Joseph Quinn, Karen L. Edwards, Thomas Montine, Vivianna M. Van Deerlin, John Trojanowski, Cyrus P. Zabetian, Alice S. Chen-Plotkin

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. Methods: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Results: Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). Interpretation: Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

Original languageEnglish (US)
Pages (from-to)15-25
Number of pages11
JournalAnnals of Clinical and Translational Neurology
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2017

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Endophenotypes
Parkinson Disease
Tremor
Genotype
Gait
Single Nucleotide Polymorphism
Phenotype
alpha-Synuclein
Precision Medicine
Brain
Cerebellum
Clinical Trials
Databases

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Cooper, C. A., Jain, N., Gallagher, M. D., Weintraub, D., Xie, S. X., Berlyand, Y., ... Chen-Plotkin, A. S. (2017). Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. Annals of Clinical and Translational Neurology, 4(1), 15-25. https://doi.org/10.1002/acn3.371

Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. / Cooper, Christine A.; Jain, Nimansha; Gallagher, Michael D.; Weintraub, Daniel; Xie, Sharon X.; Berlyand, Yosef; Espay, Alberto J.; Quinn, Joseph; Edwards, Karen L.; Montine, Thomas; Van Deerlin, Vivianna M.; Trojanowski, John; Zabetian, Cyrus P.; Chen-Plotkin, Alice S.

In: Annals of Clinical and Translational Neurology, Vol. 4, No. 1, 01.01.2017, p. 15-25.

Research output: Contribution to journalArticle

Cooper, CA, Jain, N, Gallagher, MD, Weintraub, D, Xie, SX, Berlyand, Y, Espay, AJ, Quinn, J, Edwards, KL, Montine, T, Van Deerlin, VM, Trojanowski, J, Zabetian, CP & Chen-Plotkin, AS 2017, 'Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype', Annals of Clinical and Translational Neurology, vol. 4, no. 1, pp. 15-25. https://doi.org/10.1002/acn3.371
Cooper, Christine A. ; Jain, Nimansha ; Gallagher, Michael D. ; Weintraub, Daniel ; Xie, Sharon X. ; Berlyand, Yosef ; Espay, Alberto J. ; Quinn, Joseph ; Edwards, Karen L. ; Montine, Thomas ; Van Deerlin, Vivianna M. ; Trojanowski, John ; Zabetian, Cyrus P. ; Chen-Plotkin, Alice S. / Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. In: Annals of Clinical and Translational Neurology. 2017 ; Vol. 4, No. 1. pp. 15-25.
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abstract = "Objective: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. Methods: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Results: Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). Interpretation: Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.",
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AU - Jain, Nimansha

AU - Gallagher, Michael D.

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AU - Xie, Sharon X.

AU - Berlyand, Yosef

AU - Espay, Alberto J.

AU - Quinn, Joseph

AU - Edwards, Karen L.

AU - Montine, Thomas

AU - Van Deerlin, Vivianna M.

AU - Trojanowski, John

AU - Zabetian, Cyrus P.

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N2 - Objective: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. Methods: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Results: Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). Interpretation: Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

AB - Objective: Parkinson's disease (PD) presents clinically with several motor subtypes that exhibit variable treatment response and prognosis. Here, we investigated genetic variants for their potential association with PD motor phenotype and progression. Methods: We screened 10 SNPs, previously associated with PD risk, for association with tremor-dominant (TD) versus postural-instability gait disorder (PIGD) motor subtypes. SNPs that correlated with the TD/PIGD ratio in a discovery cohort of 251 PD patients were then evaluated in a multi-site replication cohort of 559 PD patients. SNPs associated with motor phenotype in both cross-sectional cohorts were next evaluated for association with (1) rates of motor progression in a longitudinal subgroup of 230 PD patients and (2) brain alpha-synuclein (SNCA) expression in the GTEx (Genotype-Tissue Expression project) consortium database. Results: Genotype at rs356182, near SNCA, correlated with the TD/PIGD ratio in both the discovery (Bonferroni-corrected P = 0.04) and replication cohorts (P = 0.02). The rs356182 GG genotype was associated with a more tremor-predominant phenotype and predicted a slower rate of motor progression (1-point difference in annual rate of UPDRS-III motor score change, P = 0.01). The rs356182 genotype was associated with SNCA expression in the cerebellum (P = 0.005). Interpretation: Our study demonstrates that the GG genotype at rs356182 provides molecular definition for a clinically important endophenotype associated with (1) more tremor-predominant motor phenomenology, (2) slower rates of motor progression, and (3) decreased brain expression of SNCA. Such molecularly defined endophenotyping in PD may benefit both clinical trial design and tailoring of clinical care as we enter the era of precision medicine.

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