Jiang Chenyang, van der Lee Sven J, Tesi Niccolò, van der Flier Wiesje M, Tijms Betty M, Reus Lianne M
Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Neuroscience, Neurodegeneration, Amsterdam, the Netherlands.
Aging Brain. 2025 Jul 30;8:100147. doi: 10.1016/j.nbas.2025.100147. eCollection 2025.
Alzheimer's disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that and genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD ( and ) and novel ADRD-genes (, , , , , and ). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.
阿尔茨海默病及相关痴呆症（ADRD）是复杂的神经退行性疾病，其遗传基础仍未完全明确。海马体体积缩小是AD的核心特征。海马体体积也有很强的遗传成分，其遗传基础可能有助于我们理解ADRD潜在的复杂生物学机制。为了确定晚发性ADRD和双侧海马体体积之间共享的遗传风险位点，我们使用联合错误发现率（conjFDR）框架对这两个性状的现有全基因组关联研究（GWAS）数据进行了跨性状分析。对鉴定出的共享位点进行了功能注释和全表型组关联研究（PheWAS），以表征它们的生物学相关性。我们鉴定出11个独特的主要遗传位点，其中7个位点显示出不一致的方向效应（与ADRD风险增加和海马体体积较小相关的位点）。我们发现 和 基因通过影响海马体体积在ADRD中发挥作用。此外，我们在先前与AD相关的基因（ 和 ）以及新的ADRD相关基因（ 、 、 、 、 、 和 ）中观察到9个新的ADRD - 海马体位点。PheWAS结果表明，大多数共享位点与神经影像学测量、白细胞标志物、红细胞标志物和脂质有关。这项研究表明ADRD和双侧海马体体积之间存在共享的遗传基础。通过整合这两个性状的汇总统计数据，我们鉴定出了新的以及先前报道的ADRD - 海马体位点。功能分析突出了免疫细胞和脂质标志物在共享位点中的作用，表明ADRD和双侧海马体体积存在共同的神经生物学基础。
