Complex Genetics of Alzheimer's Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Genome Med. 2023 Oct 4;15(1):79. doi: 10.1186/s13073-023-01233-z.
Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.
We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.
Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.
These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
阿尔茨海默病（AD）的全基因组关联研究（GWAS）已经确定了几个风险位点，但仍有许多未知。脑脊液（CSF）生物标志物可能有助于基因发现，我们之前已经证明，六种 CSF 生物标志物（β-淀粉样蛋白、总/磷酸化 tau、NfL、YKL-40 和神经颗粒蛋白）聚类为五个主要成分（PC），每个成分代表独立的统计学生物过程。在这里，我们的目的是（1）确定与这些 CSF 图谱相关的常见遗传变异，（2）评估相关变异在 AD 病理生理学中的作用，以及（3）探索潜在的性别差异。
我们在两个多中心研究（EMIF-AD 和 ADNI）中对每个生物标志物 PC 进行了 GWAS。共有 973 名参与者（n=205 名对照组，n=546 名轻度认知障碍，n=222 名 AD）被分析了 7433949 个常见 SNPs 和 19511 个蛋白质编码基因。结构方程模型测试了生物标志物 PC 是否介导了 AD 遗传风险效应，分层和交互模型探测了性别特异性效应。
五个基因座与 CSF 图谱表现出全基因组显著关联，其中两个是新的（rs145791381[炎症]和 GRIN2D[突触功能]），三个是以前描述的（APOE、TMEM106B 和 CHI3L1）。在独立数据集的后续分析中，只有 GRIN2D 基因座支持了两个新信号，该基因座包含几个功能上有趣的候选基因。中介测试表明，APOE 中的变异与与淀粉样蛋白和 tau 病理相关的 AD 状态相关，而 TMEM106B 和 CHI3L1 中的标记物仅通过神经元损伤/炎症与 AD 相关。此外，七个基因座与 AD 生物标志物存在性别特异性关联。
这些结果表明，途径和性别特异性分析可以提高我们对 AD 遗传学的理解，并可能有助于精准医学。
