Background

Depression has been associated with a higher risk of Alzheimer’s disease (AD) in several prospective studies; however, mechanisms underlying this association remain unclear.

Methods

We examined genetic correlation between depression and AD using linkage disequilibrium score regression. We then tested for evidence of causality between depression and AD using Mendelian randomization and genome-wide association study results. Subsequently, cis and trans quantitative trait locus analyses for the depression genome-wide association study signals were performed to resolve the genetic signals to specific DNA methylation sites, brain transcripts, and proteins. These transcripts and proteins were then examined for associations with AD and its endophenotypes. Finally, the associations between depression polygenic risk score and AD endophenotypes were examined.

Results

We detected a significant genetic correlation between depression and AD, suggesting that they have a shared genetic basis. Furthermore, we found that depression had a causal role in AD through Mendelian randomization but did not find evidence for a causal role of AD on depression. Moreover, we identified 75 brain transcripts and 28 brain proteins regulated by the depression genome-wide association study signals through quantitative trait locus analyses. Of these, 46 transcripts and seven proteins were associated with rates of cognitive decline over time, AD pathologies, and AD diagnosis in two separate cohorts, thus implicating them in AD. In addition, we found that a higher depression polygenic risk score was associated with a faster decline of episodic memory over time.

Conclusions

Depression appears to have a causal role in AD, and this causal relationship is likely driven, in part, by the 53 brain transcripts and proteins identified in this study.

中文翻译：

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支持抑郁症与阿尔茨海默氏病因果关系的遗传证据

背景

多项前瞻性研究表明，抑郁症与阿尔茨海默病 (AD) 的较高风险有关；然而，这种关联的机制仍不清楚。

方法

我们使用连锁不平衡评分回归检查了抑郁症和 AD 之间的遗传相关性。然后，我们使用孟德尔随机化和全基因组关联研究结果测试了抑郁症与 AD 之间因果关系的证据。随后，对抑郁症全基因组关联研究信号进行顺式和反式数量性状位点分析，以解析特定 DNA 甲基化位点、大脑转录本和蛋白质的遗传信号。然后检查这些转录物和蛋白质与 AD 及其内表型的关联。最后，研究了抑郁症多基因风险评分与 AD 内表型之间的关联。

结果

我们发现抑郁症和 AD 之间存在显着的遗传相关性，表明它们具有共同的遗传基础。此外，我们通过孟德尔随机化发现抑郁症与 AD 存在因果关系，但没有找到 AD 与抑郁症因果关系的证据。此外，我们通过数量性状基因座分析，鉴定了 75 个大脑转录本和 28 个受抑郁症全基因组关联研究信号调节的大脑蛋白。其中，46 个转录物和 7 个蛋白质与两个不同队列中随时间推移的认知衰退率、AD 病理和 AD 诊断相关，因此将它们与 AD 相关。此外，我们发现，随着时间的推移，较高的抑郁症多基因风险评分与情景记忆的较快下降有关。

结论

抑郁症似乎与 AD 存在因果关系，这种因果关系可能部分是由本研究中发现的 53 个大脑转录本和蛋白质驱动的。