Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease
Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease
复制标题
DOI：
10.1212/wnl.0b013e318294b434
复制
发表时间：
2013-05-01
期刊：
影响因子：
9.9
通讯作者：
Chinnery, Patrick F.
中科院分区：
文献类型：
--
作者：
Hudson, Gavin;Nalls, Mike;Chinnery, Patrick F.
目的：线粒体DNA（mtDNA）和特发性帕金森病（PD）之间的先前关联一直不一致和矛盾。我们的目的是解决这些不一致性，并确定mtDNA是否在发生PD的风险中起重要作用。方法：对3，074例PD病例和5，659例种族匹配对照的138种常见mtDNA变异进行两阶段遗传关联研究，然后对6，140例PD病例和13，280例对照进行荟萃分析。在相关性研究中，m.2158T>C和m.11251A>G与发现和复制队列中PD风险降低相关。没有一个常见的欧洲mtDNA单倍型群与PD一致相关，但发现和复制队列的汇集揭示了与“超级单倍型群”JT的保护性关联。在荟萃分析中，PD的风险降低与单倍群J，K和T和超级单倍群JT，并在PD的风险增加与超级单倍群H.结论：在2阶段的关联研究线粒体DNA变异和PD，我们证实PD的风险降低与超级单倍群JT和解决这一问题在J1b水平。荟萃分析解释了先前可能通过抽样效应产生的不一致关联。单倍群J、K和T的PD风险降低反映为超单倍群HV的PD风险增加，这增加了脓毒症后的生存率。因此，mtDNA单倍型群之间的拮抗性多效性可能塑造了人类的遗传景观，导致晚年患PD的风险增加。
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.