Mitochondrial Genomic Analysis of Late Onset Alzheimer’s Disease Reveals Protective Haplogroups H6A1A/H6A1B: The Cache County Study on Memory in Aging

BackgroundAlzheimer’s disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain.
Methodology/Principal FindingsWe determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p = 0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status.
Conclusions/SignificanceOur findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.

研究背景：阿尔茨海默病（Alzheimer’s disease, AD）是痴呆最常见的病因，且AD发病风险具有家族聚集性。AD的部分家族聚集性可归因于母系遗传相较于父系遗传的优势，这一模式符合线粒体遗传的特征。目前，特异性线粒体DNA（mitochondrial DNA, mtDNA）变异及单倍群（haplogroup）在AD发病风险中的作用仍不明确。
研究方法与主要结果：我们对犹他州北部以人群为基础的前瞻性队列研究——卡什县记忆衰老研究（Cache County Study on Memory in Aging）中的1007名参与者完成了线粒体全基因组测序。AD诊断采用多阶段流程，由临床专家小组通过临床检查与病例复核确定。我们采用基于单倍型网络的统计学稳健方法TreeScanning分析线粒体DNA测序数据。携带主要线粒体单倍型H6A1A与H6A1B的参与者，其AD发病风险显著降低（p=0.017，经多重比较校正）。这两种保护性单倍型由三个变异位点定义：m.3915G>A、m.4727A>G及m.9380G>A。上述三个变异分属两个不同的主要单倍群：m.4727A>G与m.9380G>A共同构成单倍型H6A1，而m.3915G>A被认为可定义单倍群H6A。另有额外变异用于区分H6A1A与H6A1B，但这些变异均与AD的病例-对照状态无显著关联。
研究结论与意义：本研究结果显示，携带线粒体DNA单倍型H6A1A与H6A1B的个体，其AD发病风险更低。本研究是目前首个采用完整线粒体基因组测序数据的大规模相关研究，但相关单倍型的功能意义仍未明确，仍需在其他研究中开展重复验证。