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
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/genetics
KW - Genetic Association Studies/methods
KW - Genetic Predisposition to Disease
KW - Genetic Variation/genetics
KW - Humans
KW - Parkinson Disease/genetics
KW - Risk
KW - United Kingdom
U2 - 10.1212/WNL.0b013e318294b434
DO - 10.1212/WNL.0b013e318294b434
M3 - Article
C2 - 23645593
SN - 0028-3878
VL - 80
SP - 2042
EP - 2048
JO - Neurology
JF - Neurology
IS - 22
ER -