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

Research output: Contribution to journalArticle

Authors

  • Gavin Hudson
  • 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

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)2042-8
Number of pages7
JournalNeurology
Volume80
Issue number22
Publication statusPublished - 28 May 2013

Keywords

  • Cohort Studies, DNA, Mitochondrial, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Great Britain, Humans, Parkinson Disease, Risk