School of Computer Science, Northeast Electric Power University, 169 Changchun Street, Jilin, 132012, China.
College of Intelligent Systems Science and Engineering, Harbin Engineering University, 145 Nantong Street, Harbin, China.
Sci Rep. 2024 Feb 17;14(1):3984. doi: 10.1038/s41598-024-54541-8.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly worldwide. The exact etiology of AD, particularly its genetic mechanisms, remains incompletely understood. Traditional genome-wide association studies (GWAS), which primarily focus on single-nucleotide polymorphisms (SNPs) with main effects, provide limited explanations for the "missing heritability" of AD, while there is growing evidence supporting the important role of epistasis. In this study, we performed a genome-wide SNP-SNP interaction detection using a linear regression model and employed multiple GPUs for parallel computing, significantly enhancing the speed of whole-genome analysis. The cerebrospinal fluid (CSF) phosphorylated tau (P-tau)/amyloid-[Formula: see text] (A[Formula: see text]) ratio was used as a quantitative trait (QT) to enhance statistical power. Age, gender, and clinical diagnosis were included as covariates to control for potential non-genetic factors influencing AD. We identified 961 pairs of statistically significant SNP-SNP interactions, explaining a high-level variance of P-tau/A[Formula: see text] level, all of which exhibited marginal main effects. Additionally, we replicated 432 previously reported AD-related genes and found 11 gene-gene interaction pairs overlapping with the protein-protein interaction (PPI) network. Our findings may contribute to partially explain the "missing heritability" of AD. The identified subnetwork may be associated with synaptic dysfunction, Wnt signaling pathway, oligodendrocytes, inflammation, hippocampus, and neuronal cells.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是全球老年人中最常见的痴呆症病因。AD 的确切病因，尤其是其遗传机制，仍不完全清楚。传统的全基因组关联研究（GWAS）主要集中在具有主要效应的单核苷酸多态性（SNP）上，对 AD 的“遗传缺失”提供了有限的解释，而越来越多的证据支持上位性的重要作用。在这项研究中，我们使用线性回归模型进行了全基因组 SNP-SNP 相互作用检测，并采用多个 GPU 进行并行计算，显著提高了全基因组分析的速度。脑脊液（CSF）磷酸化 tau（P-tau）/淀粉样蛋白-[Formula: see text]（A[Formula: see text]）比值被用作定量性状（QT），以提高统计功效。年龄、性别和临床诊断被纳入协变量，以控制影响 AD 的潜在非遗传因素。我们确定了 961 对具有统计学意义的 SNP-SNP 相互作用，这些相互作用解释了 P-tau/A[Formula: see text]水平的高水平方差，所有这些相互作用都表现出边缘主要效应。此外，我们复制了 432 个先前报道的与 AD 相关的基因，并发现了 11 个与蛋白质-蛋白质相互作用（PPI）网络重叠的基因-基因相互作用对。我们的发现可能有助于部分解释 AD 的“遗传缺失”。鉴定出的子网络可能与突触功能障碍、Wnt 信号通路、少突胶质细胞、炎症、海马体和神经元细胞有关。
