Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease

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Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. / Hudson, Gavin; Nalls, Mike; Evans, Jonathan R; Breen, David P; Winder-Rhodes, Sophie; Morrison, Karen E; Morris, Huw R; Williams-Gray, Caroline H; Barker, Roger A; Singleton, Andrew B; Hardy, John; Wood, Nicholas E; Burn, David J; Chinnery, Patrick F; Morrison, Karen.

In: Neurology, Vol. 80, No. 22, 28.05.2013, p. 2042-8.

Research output: Contribution to journalArticle

Harvard

Hudson, G, Nalls, M, Evans, JR, Breen, DP, Winder-Rhodes, S, Morrison, KE, Morris, HR, Williams-Gray, CH, Barker, RA, Singleton, AB, Hardy, J, Wood, NE, Burn, DJ, Chinnery, PF & Morrison, K 2013, 'Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease', Neurology, vol. 80, no. 22, pp. 2042-8. https://doi.org/10.1212/WNL.0b013e318294b434

APA

Hudson, G., Nalls, M., Evans, J. R., Breen, D. P., Winder-Rhodes, S., Morrison, K. E., Morris, H. R., Williams-Gray, C. H., Barker, R. A., Singleton, A. B., Hardy, J., Wood, N. E., Burn, D. J., Chinnery, P. F., & Morrison, K. (2013). Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology, 80(22), 2042-8. https://doi.org/10.1212/WNL.0b013e318294b434

Vancouver

Hudson G, Nalls M, Evans JR, Breen DP, Winder-Rhodes S, Morrison KE et al. Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology. 2013 May 28;80(22):2042-8. https://doi.org/10.1212/WNL.0b013e318294b434

Author

Hudson, Gavin ; Nalls, Mike ; Evans, Jonathan R ; Breen, David P ; Winder-Rhodes, Sophie ; Morrison, Karen E ; Morris, Huw R ; Williams-Gray, Caroline H ; Barker, Roger A ; Singleton, Andrew B ; Hardy, John ; Wood, Nicholas E ; Burn, David J ; Chinnery, Patrick F ; Morrison, Karen. / Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. In: Neurology. 2013 ; Vol. 80, No. 22. pp. 2042-8.

Bibtex

@article{68dfe6936de4413eba106f1ecb8fe718,
title = "Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease",
abstract = "OBJECTIVES: Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD.METHODS: Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.RESULTS: In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with {"}super-haplogroup{"} JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.CONCLUSIONS: In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.",
keywords = "Cohort Studies, DNA, Mitochondrial, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Great Britain, Humans, Parkinson Disease, Risk",
author = "Gavin Hudson and Mike Nalls and Evans, {Jonathan R} and Breen, {David P} and Sophie Winder-Rhodes and Morrison, {Karen E} and Morris, {Huw R} and Williams-Gray, {Caroline H} and Barker, {Roger A} and Singleton, {Andrew B} and John Hardy and Wood, {Nicholas E} and Burn, {David J} and Chinnery, {Patrick F} and Karen Morrison",
year = "2013",
month = may
day = "28",
doi = "10.1212/WNL.0b013e318294b434",
language = "English",
volume = "80",
pages = "2042--8",
journal = "Neurology",
issn = "0028-3878",
publisher = "American Academy of Neurology",
number = "22",

}

RIS

TY - JOUR

T1 - Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease

AU - Hudson, Gavin

AU - Nalls, Mike

AU - Evans, Jonathan R

AU - Breen, David P

AU - Winder-Rhodes, Sophie

AU - Morrison, Karen E

AU - Morris, Huw R

AU - Williams-Gray, Caroline H

AU - Barker, Roger A

AU - Singleton, Andrew B

AU - Hardy, John

AU - Wood, Nicholas E

AU - Burn, David J

AU - Chinnery, Patrick F

AU - Morrison, Karen

PY - 2013/5/28

Y1 - 2013/5/28

N2 - OBJECTIVES: Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD.METHODS: Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.RESULTS: In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with "super-haplogroup" JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.CONCLUSIONS: In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.

AB - OBJECTIVES: Previous associations between mitochondrial DNA (mtDNA) and idiopathic Parkinson disease (PD) have been inconsistent and contradictory. Our aim was to resolve these inconsistencies and determine whether mtDNA has a significant role in the risk of developing PD.METHODS: Two-stage genetic association study of 138 common mtDNA variants in 3,074 PD cases and 5,659 ethnically matched controls followed by meta-analysis of 6,140 PD cases and 13,280 controls.RESULTS: In the association study, m.2158T>C and m.11251A>G were associated with a reduced risk of PD in both the discovery and replication cohorts. None of the common European mtDNA haplogroups were consistently associated with PD, but pooling of discovery and replication cohorts revealed a protective association with "super-haplogroup" JT. In the meta-analysis, there was a reduced risk of PD with haplogroups J, K, and T and super-haplogroup JT, and an increase in the risk of PD with super-haplogroup H.CONCLUSIONS: In a 2-stage association study of mtDNA variants and PD, we confirm the reduced risk of PD with super-haplogroup JT and resolve this at the J1b level. Meta-analysis explains the previous inconsistent associations that likely arise through sampling effects. The reduced risk of PD with haplogroups J, K, and T is mirrored by an increased risk of PD in super-haplogroup HV, which increases survival after sepsis. Antagonistic pleiotropy between mtDNA haplogroups may thus be shaping the genetic landscape in humans, leading to an increased risk of PD in later life.

KW - Cohort Studies

KW - DNA, Mitochondrial

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Great Britain

KW - Humans

KW - Parkinson Disease

KW - Risk

U2 - 10.1212/WNL.0b013e318294b434

DO - 10.1212/WNL.0b013e318294b434

M3 - Article

C2 - 23645593

VL - 80

SP - 2042

EP - 2048

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 22

ER -