Center for Human Genetics and Research, Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA.
J Alzheimers Dis. 2014;38(1):145-54. doi: 10.3233/JAD-130989.
The genetic etiology of late-onset Alzheimer's disease (LOAD) has proven complex, involving clinical and genetic heterogeneity and gene-gene interactions. Recent genome wide association studies in LOAD have led to the discovery of novel genetic risk factors; however, the investigation of gene-gene interactions has been limited. Conventional genetic studies often use binary disease status as the primary phenotype, but for complex brain-based diseases, neuroimaging data can serve as quantitative endophenotypes that correlate with disease status and closely reflect pathological changes. In the Alzheimer's Disease Neuroimaging Initiative cohort, we tested for association of genetic interactions with longitudinal MRI measurements of the inferior lateral ventricles (ILVs), which have repeatedly shown a relationship to LOAD status and progression. We performed linear regression to evaluate the ability of pathway-derived SNP-SNP pairs to predict the slope of change in volume of the ILVs. After Bonferroni correction, we identified four significant interactions in the right ILV (RILV) corresponding to gene-gene pairs SYNJ2-PI4KA, PARD3-MYH2, PDE3A-ABHD12B, and OR2L13-PRKG1 and one significant interaction in the left ILV (LILV) corresponding to SYNJ2-PI4KA. The SNP-SNP interaction corresponding to SYNJ2-PI4KA was identical in the RILV and LILV and was the most significant interaction in each (RILV: p = 9.13 × 10(-12); LILV: p = 8.17 × 10(-13)). Both genes belong to the inositol phosphate signaling pathway which has been previously associated with neurodegeneration in AD and we discuss the possibility that perturbation of this pathway results in a down-regulation of the Akt cell survival pathway and, thereby, decreased neuronal survival, as reflected by increased volume of the ventricles.
晚发性阿尔茨海默病（LOAD）的遗传病因学已被证明非常复杂，涉及临床和遗传异质性以及基因-基因相互作用。最近在 LOAD 中的全基因组关联研究导致了新的遗传风险因素的发现；然而，对基因-基因相互作用的研究受到限制。传统的遗传研究通常使用二元疾病状态作为主要表型，但对于复杂的基于大脑的疾病，神经影像学数据可以作为与疾病状态相关并密切反映病理变化的定量内表型。在阿尔茨海默病神经影像学倡议队列中，我们测试了遗传相互作用与下外侧脑室（ILVs）的纵向 MRI 测量值之间的关联，这些测量值反复显示与 LOAD 状态和进展相关。我们进行了线性回归，以评估途径衍生的 SNP-SNP 对预测 ILVs 体积变化斜率的能力。经过 Bonferroni 校正，我们在右 ILV（RILV）中确定了四个与基因-基因对 SYNJ2-PI4KA、PARD3-MYH2、PDE3A-ABHD12B 和 OR2L13-PRKG1 相关的显着相互作用，以及左 ILV（LILV）中一个与 SYNJ2-PI4KA 相关的显着相互作用。与 SYNJ2-PI4KA 对应的 SNP-SNP 相互作用在 RILV 和 LILV 中是相同的，并且在每个（RILV：p = 9.13×10(-12)；LILV：p = 8.17×10(-13)）中都是最显着的相互作用。这两个基因都属于肌醇磷酸信号通路，该通路先前与 AD 中的神经退行性变有关，我们讨论了这种通路的干扰导致 Akt 细胞存活通路下调，从而导致神经元存活减少，脑室体积增加的可能性。
