PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease

Gary W Beecham, Dennis W. Dickson, William K Scott, Eden R Martin, Gerard Schellenberg, Karen Nuytemans, Eric B. Larson, Joseph D. Buxbaum, John Q. Trojanowski, Vivianna M. Van Deerlin, Howard I. Hurtig, Deborah C Mash, Thomas G. Beach, Juan C. Troncoso, Olga Pletnikova, Matthew P. Frosch, Bernardino Ghetti, Tatiana M. Foroud, Lawrence S. Honig, Karen MarderJean Paul Vonsattel, Samuel M. Goldman, Harry V. Vinters, Owen A. Ross, Zbigniew K. Wszolek, Liyong Wang, Derek M Dykxhoorn, Margaret A Pericak-Vance, Thomas J. Montine, James B. Leverenz, Ted M. Dawson, Jeffery M Vance

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p 6.2 × 10-8). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

Original languageEnglish (US)
Pages (from-to)972-980
Number of pages9
JournalNeurology
Volume84
Issue number10
DOIs
StatePublished - Mar 10 2015

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Parkinson Disease
Genome-Wide Association Study
Haplotypes
Genetic Heterogeneity
Chromosomes, Human, Pair 1
Linkage Disequilibrium
Genetic Association Studies
Parkinson Disease 10
Genes
Single Nucleotide Polymorphism
Autopsy
Research

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease. / Beecham, Gary W; Dickson, Dennis W.; Scott, William K; Martin, Eden R; Schellenberg, Gerard; Nuytemans, Karen; Larson, Eric B.; Buxbaum, Joseph D.; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Hurtig, Howard I.; Mash, Deborah C; Beach, Thomas G.; Troncoso, Juan C.; Pletnikova, Olga; Frosch, Matthew P.; Ghetti, Bernardino; Foroud, Tatiana M.; Honig, Lawrence S.; Marder, Karen; Vonsattel, Jean Paul; Goldman, Samuel M.; Vinters, Harry V.; Ross, Owen A.; Wszolek, Zbigniew K.; Wang, Liyong; Dykxhoorn, Derek M; Pericak-Vance, Margaret A; Montine, Thomas J.; Leverenz, James B.; Dawson, Ted M.; Vance, Jeffery M.

In: Neurology, Vol. 84, No. 10, 10.03.2015, p. 972-980.

Research output: Contribution to journalArticle

Beecham, GW, Dickson, DW, Scott, WK, Martin, ER, Schellenberg, G, Nuytemans, K, Larson, EB, Buxbaum, JD, Trojanowski, JQ, Van Deerlin, VM, Hurtig, HI, Mash, DC, Beach, TG, Troncoso, JC, Pletnikova, O, Frosch, MP, Ghetti, B, Foroud, TM, Honig, LS, Marder, K, Vonsattel, JP, Goldman, SM, Vinters, HV, Ross, OA, Wszolek, ZK, Wang, L, Dykxhoorn, DM, Pericak-Vance, MA, Montine, TJ, Leverenz, JB, Dawson, TM & Vance, JM 2015, 'PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease', Neurology, vol. 84, no. 10, pp. 972-980. https://doi.org/10.1212/WNL.0000000000001332
Beecham, Gary W ; Dickson, Dennis W. ; Scott, William K ; Martin, Eden R ; Schellenberg, Gerard ; Nuytemans, Karen ; Larson, Eric B. ; Buxbaum, Joseph D. ; Trojanowski, John Q. ; Van Deerlin, Vivianna M. ; Hurtig, Howard I. ; Mash, Deborah C ; Beach, Thomas G. ; Troncoso, Juan C. ; Pletnikova, Olga ; Frosch, Matthew P. ; Ghetti, Bernardino ; Foroud, Tatiana M. ; Honig, Lawrence S. ; Marder, Karen ; Vonsattel, Jean Paul ; Goldman, Samuel M. ; Vinters, Harry V. ; Ross, Owen A. ; Wszolek, Zbigniew K. ; Wang, Liyong ; Dykxhoorn, Derek M ; Pericak-Vance, Margaret A ; Montine, Thomas J. ; Leverenz, James B. ; Dawson, Ted M. ; Vance, Jeffery M. / PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease. In: Neurology. 2015 ; Vol. 84, No. 10. pp. 972-980.
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abstract = "Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p 6.2 × 10-8). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.",
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T1 - PARK10 is a major locus for sporadic neuropathologically confirmed Parkinson disease

AU - Beecham, Gary W

AU - Dickson, Dennis W.

AU - Scott, William K

AU - Martin, Eden R

AU - Schellenberg, Gerard

AU - Nuytemans, Karen

AU - Larson, Eric B.

AU - Buxbaum, Joseph D.

AU - Trojanowski, John Q.

AU - Van Deerlin, Vivianna M.

AU - Hurtig, Howard I.

AU - Mash, Deborah C

AU - Beach, Thomas G.

AU - Troncoso, Juan C.

AU - Pletnikova, Olga

AU - Frosch, Matthew P.

AU - Ghetti, Bernardino

AU - Foroud, Tatiana M.

AU - Honig, Lawrence S.

AU - Marder, Karen

AU - Vonsattel, Jean Paul

AU - Goldman, Samuel M.

AU - Vinters, Harry V.

AU - Ross, Owen A.

AU - Wszolek, Zbigniew K.

AU - Wang, Liyong

AU - Dykxhoorn, Derek M

AU - Pericak-Vance, Margaret A

AU - Montine, Thomas J.

AU - Leverenz, James B.

AU - Dawson, Ted M.

AU - Vance, Jeffery M

PY - 2015/3/10

Y1 - 2015/3/10

N2 - Objective: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Methods: Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. Results: A small region on chromosome 1 was strongly associated with PD (rs10788972; p 6.2 × 10-8). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. Conclusions: We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.

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