NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Neurobiol Dis. 2023 Jul;183:106174. doi: 10.1016/j.nbd.2023.106174. Epub 2023 Jun 5.
Neuroinflammation is involved in the pathophysiology of Alzheimer's disease (AD), including immune-linked genetic variants and molecular pathways, microglia and astrocytes. Multiple Sclerosis (MS) is a chronic, immune-mediated disease with genetic and environmental risk factors and neuropathological features. There are clinical and pathobiological similarities between AD and MS. Here, we investigated shared genetic susceptibility between AD and MS to identify putative pathological mechanisms shared between neurodegeneration and the immune system.
We analysed GWAS data for late-onset AD (N cases = 64,549, N controls = 634,442) and MS (N cases = 14,802, N controls = 26,703). Gaussian causal mixture modelling (MiXeR) was applied to characterise the genetic architecture and overlap between AD and MS. Local genetic correlation was investigated with Local Analysis of [co]Variant Association (LAVA). The conjunctional false discovery rate (conjFDR) framework was used to identify the specific shared genetic loci, for which functional annotation was conducted with FUMA and Open Targets.
MiXeR analysis showed comparable polygenicities for AD and MS (approximately 1800 trait-influencing variants) and genetic overlap with 20% of shared trait-influencing variants despite negligible genetic correlation (rg = 0.03), suggesting mixed directions of genetic effects across shared variants. conjFDR analysis identified 16 shared genetic loci, with 8 having concordant direction of effects in AD and MS. Annotated genes in shared loci were enriched in molecular signalling pathways involved in inflammation and the structural organisation of neurons.
Despite low global genetic correlation, the current results provide evidence for polygenic overlap between AD and MS. The shared loci between AD and MS were enriched in pathways involved in inflammation and neurodegeneration, highlighting new opportunities for future investigation.
神经炎症参与阿尔茨海默病（AD）的病理生理学，包括免疫相关的遗传变异和分子途径、小胶质细胞和星形胶质细胞。多发性硬化症（MS）是一种慢性、免疫介导的疾病，具有遗传和环境风险因素以及神经病理学特征。AD 和 MS 之间存在临床和病理生物学上的相似性。在这里，我们研究了 AD 和 MS 之间的共同遗传易感性，以确定神经退行性变和免疫系统之间共享的潜在病理机制。
我们分析了晚发性 AD（病例 N=64549，对照 N=63442）和 MS（病例 N=14802，对照 N=26703）的 GWAS 数据。高斯因果混合模型（MiXeR）用于描述 AD 和 MS 的遗传结构和重叠。局部遗传相关性通过局部分析 [共同]变异关联（LAVA）进行研究。联合假发现率（conjFDR）框架用于识别特定的共享遗传位点，并使用 FUMA 和 Open Targets 对其进行功能注释。
MiXeR 分析表明，AD 和 MS 的多基因性相似（大约有 1800 个影响性状的变异），并且尽管遗传相关性很小（rg=0.03），但存在 20%的共享影响性状的变异，表明共享变异的遗传效应方向混合。conjFDR 分析确定了 16 个共享遗传位点，其中 8 个在 AD 和 MS 中具有一致的效应方向。共享位点的注释基因在涉及炎症和神经元结构组织的分子信号通路中富集。
尽管总体遗传相关性较低，但目前的结果为 AD 和 MS 之间的多基因重叠提供了证据。AD 和 MS 之间的共享位点在炎症和神经退行性变相关的通路中富集，突出了未来研究的新机会。
