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. Multiple lines of evidence implicate mitochondria in the pathogenesis of idiopathic Parkinson disease (PD). A defect of respiratory chain complex I has been documented in the substantia nigra of postmortem PD brains, 1 and the potent complex I inhibitor MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes parkinsonism and nigrostriatal dopaminergic degeneration in humans.2 Exposing rats to the complex I inhibitor rotenone causes tremor and rigidity with associated loss of substantia nigra neurons and aggregation of a-synuclein, a major constituent of Lewy bodies, which characterize the neuropathology of PD.3 Furthermore, several monogenic forms of PD are due to mutations in genes coding for mitochondrial proteins or mitochondrial maintenance/autophagy (including PARK2, 4 PINK1, 5 and DJ 5), which compromise oxidative phosphorylation.Mitochondrial DNA (mtDNA) codes for 13 respiratory chain proteins that are essential for the synthesis of the intracellular energy source adenosine triphosphate. Point mutations of mtDNA compromise oxidative phosphorylation and cause severe multisystem neurologic disorders with

The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease

“…At the other extreme, common population polymorphisms have a small effect on the risk of developing common human diseases. The most compelling case is for Parkinson disease, and the results of several large studies implicate common mtDNA variants in the pathogenesis of this disease 106 . The same variants might also contribute to the risk of developing several human diseases that share common mitochondrial mechanisms 12 .…”

The Ageing Brain, Mitochondria and Neurodegeneration

“…Smaller studies have reported a contradictory increase in PD risk with haplogroup J [ 96 ], but sample number and genetic heterogeneity, critically misunderstood in the highly mutable mtDNA [ 97 ], may account for this disparity. More recently, a much larger study and meta-analysis confi rmed the role of haplogroup J/K in reducing the risk of PD [ 98 ], an effect which was replicated in a follow-up study later [ 99 ]. A meta-analysis of all available mtDNA-PD data was able to identify that the phylogenetically linked H/V haplogroups increased the risk of PD [ 99 ].…”

Применение Эндотелийстабилизирующих Препаратов (Капикор) В Комплексной Патогенетической Терапии Больных Болезнью Паркинсона (Клинико-Экспериментальное Исследование)

“…Кроме того, увели-чение экспрессии гена паркина свидетельствует о его влиянии на нейропротекторную функцию, регуляцию проявлений оксидативного стресса и митохондриаль-ного биогенеза [18][19][20].…”