SNCA variant associated with Parkinson disease and plasma α-synuclein level

Ignacio F. Mata, Min Shi, Pinky Agarwal, Kathryn (Kathy) Chung, Karen L. Edwards, Stewart A. Factor, Douglas R. Galasko, Carmen Ginghina, Alida Griffith, Donald S. Higgins, Denise M. Kay, Hojoong Kim, James B. Leverenz, Joseph Quinn, John W. Roberts, Ali Samii, Katherine W. Snapinn, Debby W. Tsuang, Dora Yearout, Jing Zhang & 2 others Haydeh Payami, Cyrus P. Zabetian

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Background: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. Objectives: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. Design: Two-tiered analysis. Setting: Academic research. Patients: Patients and control subjects from the NeuroGenetics Research Consortium. Main Outcome Measures: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. Results: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α=.05). Of these, 4 weresuccessfullyreplicatedintier2.Inthecombinedsample, themostsignificantmarkerwasrs356219 (odds ratio, 1.41; 95%confidence interval, 1.28-1.55;P=1.6×10-12), located approximately 9 kilobases downstream from the gene. A regressionmodelcontainingrs356219alonebest fitthedata. Thelinkage disequilibrium correlation coefficient between thisSNPand REP1 was low (r2=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P=.005). Conclusions: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

Original languageEnglish (US)
Pages (from-to)1350-1356
Number of pages7
JournalArchives of Neurology
Volume67
Issue number11
DOIs
StatePublished - Nov 2010

Fingerprint

Synucleins
Parkinson Disease
Single Nucleotide Polymorphism
Research
Plasma
Parkinson's Disease
Disease Susceptibility
Genes
Odds Ratio
Genotype
Outcome Assessment (Health Care)
Polymorphism
Confidence Intervals

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Mata, I. F., Shi, M., Agarwal, P., Chung, K. K., Edwards, K. L., Factor, S. A., ... Zabetian, C. P. (2010). SNCA variant associated with Parkinson disease and plasma α-synuclein level. Archives of Neurology, 67(11), 1350-1356. https://doi.org/10.1001/archneurol.2010.279

SNCA variant associated with Parkinson disease and plasma α-synuclein level. / Mata, Ignacio F.; Shi, Min; Agarwal, Pinky; Chung, Kathryn (Kathy); Edwards, Karen L.; Factor, Stewart A.; Galasko, Douglas R.; Ginghina, Carmen; Griffith, Alida; Higgins, Donald S.; Kay, Denise M.; Kim, Hojoong; Leverenz, James B.; Quinn, Joseph; Roberts, John W.; Samii, Ali; Snapinn, Katherine W.; Tsuang, Debby W.; Yearout, Dora; Zhang, Jing; Payami, Haydeh; Zabetian, Cyrus P.

In: Archives of Neurology, Vol. 67, No. 11, 11.2010, p. 1350-1356.

Research output: Contribution to journalArticle

Mata, IF, Shi, M, Agarwal, P, Chung, KK, Edwards, KL, Factor, SA, Galasko, DR, Ginghina, C, Griffith, A, Higgins, DS, Kay, DM, Kim, H, Leverenz, JB, Quinn, J, Roberts, JW, Samii, A, Snapinn, KW, Tsuang, DW, Yearout, D, Zhang, J, Payami, H & Zabetian, CP 2010, 'SNCA variant associated with Parkinson disease and plasma α-synuclein level', Archives of Neurology, vol. 67, no. 11, pp. 1350-1356. https://doi.org/10.1001/archneurol.2010.279
Mata, Ignacio F. ; Shi, Min ; Agarwal, Pinky ; Chung, Kathryn (Kathy) ; Edwards, Karen L. ; Factor, Stewart A. ; Galasko, Douglas R. ; Ginghina, Carmen ; Griffith, Alida ; Higgins, Donald S. ; Kay, Denise M. ; Kim, Hojoong ; Leverenz, James B. ; Quinn, Joseph ; Roberts, John W. ; Samii, Ali ; Snapinn, Katherine W. ; Tsuang, Debby W. ; Yearout, Dora ; Zhang, Jing ; Payami, Haydeh ; Zabetian, Cyrus P. / SNCA variant associated with Parkinson disease and plasma α-synuclein level. In: Archives of Neurology. 2010 ; Vol. 67, No. 11. pp. 1350-1356.
@article{8672708a90be4f6e9123e5cd8a7d7bda,
title = "SNCA variant associated with Parkinson disease and plasma α-synuclein level",
abstract = "Background: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. Objectives: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. Design: Two-tiered analysis. Setting: Academic research. Patients: Patients and control subjects from the NeuroGenetics Research Consortium. Main Outcome Measures: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. Results: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α=.05). Of these, 4 weresuccessfullyreplicatedintier2.Inthecombinedsample, themostsignificantmarkerwasrs356219 (odds ratio, 1.41; 95{\%}confidence interval, 1.28-1.55;P=1.6×10-12), located approximately 9 kilobases downstream from the gene. A regressionmodelcontainingrs356219alonebest fitthedata. Thelinkage disequilibrium correlation coefficient between thisSNPand REP1 was low (r2=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P=.005). Conclusions: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.",
author = "Mata, {Ignacio F.} and Min Shi and Pinky Agarwal and Chung, {Kathryn (Kathy)} and Edwards, {Karen L.} and Factor, {Stewart A.} and Galasko, {Douglas R.} and Carmen Ginghina and Alida Griffith and Higgins, {Donald S.} and Kay, {Denise M.} and Hojoong Kim and Leverenz, {James B.} and Joseph Quinn and Roberts, {John W.} and Ali Samii and Snapinn, {Katherine W.} and Tsuang, {Debby W.} and Dora Yearout and Jing Zhang and Haydeh Payami and Zabetian, {Cyrus P.}",
year = "2010",
month = "11",
doi = "10.1001/archneurol.2010.279",
language = "English (US)",
volume = "67",
pages = "1350--1356",
journal = "Archives of Neurology",
issn = "0003-9942",
publisher = "American Medical Association",
number = "11",

}

TY - JOUR

T1 - SNCA variant associated with Parkinson disease and plasma α-synuclein level

AU - Mata, Ignacio F.

AU - Shi, Min

AU - Agarwal, Pinky

AU - Chung, Kathryn (Kathy)

AU - Edwards, Karen L.

AU - Factor, Stewart A.

AU - Galasko, Douglas R.

AU - Ginghina, Carmen

AU - Griffith, Alida

AU - Higgins, Donald S.

AU - Kay, Denise M.

AU - Kim, Hojoong

AU - Leverenz, James B.

AU - Quinn, Joseph

AU - Roberts, John W.

AU - Samii, Ali

AU - Snapinn, Katherine W.

AU - Tsuang, Debby W.

AU - Yearout, Dora

AU - Zhang, Jing

AU - Payami, Haydeh

AU - Zabetian, Cyrus P.

PY - 2010/11

Y1 - 2010/11

N2 - Background: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. Objectives: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. Design: Two-tiered analysis. Setting: Academic research. Patients: Patients and control subjects from the NeuroGenetics Research Consortium. Main Outcome Measures: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. Results: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α=.05). Of these, 4 weresuccessfullyreplicatedintier2.Inthecombinedsample, themostsignificantmarkerwasrs356219 (odds ratio, 1.41; 95%confidence interval, 1.28-1.55;P=1.6×10-12), located approximately 9 kilobases downstream from the gene. A regressionmodelcontainingrs356219alonebest fitthedata. Thelinkage disequilibrium correlation coefficient between thisSNPand REP1 was low (r2=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P=.005). Conclusions: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

AB - Background: A functional repeat polymorphism in the SNCA promoter (REP1) conveys susceptibility for Parkinson disease (PD). There is also increasing evidence that single-nucleotide polymorphisms (SNPs) elsewhere in the gene are associated with PD risk. Objectives: To further explore the association of common SNCA SNPs with PD susceptibility, to determine whether evidence of allelic heterogeneity exists, and to examine the correlation between PD-associated variants and plasma α-synuclein levels. Design: Two-tiered analysis. Setting: Academic research. Patients: Patients and control subjects from the NeuroGenetics Research Consortium. Main Outcome Measures: We performed a 2-tiered analysis of 1956 patients with PD and 2112 controls from the NeuroGenetics Research Consortium using a comprehensive tag SNP approach. Previously published REP1 genotypes were also included. Plasma α-synuclein was assayed in 86 patients with PD and 78 controls using a highly sensitive Luminex assay. Results: Five of 15 SNPs genotyped were associated with PD under an additive model in tier 1 (α=.05). Of these, 4 weresuccessfullyreplicatedintier2.Inthecombinedsample, themostsignificantmarkerwasrs356219 (odds ratio, 1.41; 95%confidence interval, 1.28-1.55;P=1.6×10-12), located approximately 9 kilobases downstream from the gene. A regressionmodelcontainingrs356219alonebest fitthedata. Thelinkage disequilibrium correlation coefficient between thisSNPand REP1 was low (r2=0.09). The risk-associated Callele of rs356219 was also correlated with higher transformed plasma α-synuclein levels in patients under an adjusted additive model (P=.005). Conclusions: Our data suggest that 1 or more unidentified functional SNCA variants modify risk for PD and that the effect is larger than and independent of REP1. This variant(s), tagged by rs356219, might act by upregulating SNCA expression in a dose-dependent manner.

UR - http://www.scopus.com/inward/record.url?scp=78149489129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78149489129&partnerID=8YFLogxK

U2 - 10.1001/archneurol.2010.279

DO - 10.1001/archneurol.2010.279

M3 - Article

VL - 67

SP - 1350

EP - 1356

JO - Archives of Neurology

JF - Archives of Neurology

SN - 0003-9942

IS - 11

ER -