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Meta-Analysis
. 2013 May 28;80(22):2042-8.
doi: 10.1212/WNL.0b013e318294b434. Epub 2013 May 3.

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

Gavin Hudson  1 , Mike Nalls, Jonathan R Evans, David P Breen, Sophie Winder-Rhodes, Karen E Morrison, Huw R Morris, Caroline H Williams-Gray, Roger A Barker, Andrew B Singleton, John Hardy, Nicholas E Wood, David J Burn, Patrick F Chinnery
Affiliations
Meta-Analysis

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

Gavin Hudson et al. Neurology. .

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.

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Figures

Figure 1
Figure 1. Meta-analysis of previously reported PD and mtDNA haplogroup associations and the data from this study
Meta-analysis of our data and published European mtDNA haplogroup vs PD associations in isolation. Discovery = Hudson et al., PD1; replication = Hudson et al., PD2. Boxes are proportional to study size, and fixed-model meta-analysis is denoted by a diamond symbol. CI = confidence interval; L95 = lower 95% CI; mtDNA = mitochondrial DNA; OR = odds ratio; PD = Parkinson disease; U95 = upper 95% CI.
Figure 2
Figure 2. Meta-analysis of previously reported PD and mtDNA “super-haplogroup” associations and the data from this study
Meta-analysis of our data and published European mtDNA haplogroup vs PD associations when combined into super-haplogroups. Discovery = Hudson et al., PD1; replication = Hudson et al., PD2. Boxes are proportional to study size, and fixed-model meta-analysis is denoted by a diamond symbol. CI = confidence interval; L95 = lower 95% CI; mtDNA = mitochondrial DNA; OR = odds ratio; PD = Parkinson disease; U95 = upper 95% CI.
See this image and copyright information in PMC

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