Department of Biomedical Engineering, Hanyang University, Seoul, Korea.
Department of Neurology, Seoul National University College of Medicine and Clinical Neuroscience Center of Seoul National University Bundang Hospital, Seongnam, Korea.
J Alzheimers Dis. 2020;75(2):531-545. doi: 10.3233/JAD-191175.
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by a heterogeneous distribution of pathological changes in the brain. Cortical thickness is one of the most sensitive imaging biomarkers for AD representing structural atrophy. The purpose of this study is to identify novel genes associated with cortical thickness. We measured the whole-brain mean cortical thickness from magnetic resonance imaging (MRI) scans in 919 subjects from the Alzheimer's Disease Neuroimaging Initiative cohort, including 163 AD patients, 488 mild cognitive impairment patients, and 268 cognitively normal participants. Based on the single-nucleotide polymorphism (SNP)-based genome-wide association study, we performed gene-based association analysis for mean cortical thickness. Furthermore, we performed expression quantitative trait loci, protein-protein interaction network, and pathway analysis to identify biologically functional information. We identified four genes (B4GALNT1, RAB44, LOC101927583, and SLC26A10), two pathways (cyclin-dependent protein kinase holoenzyme complex and nuclear cyclin-dependent protein kinase holoenzyme complex), and one protein-protein interaction (B4GALNT1 and GALNT8 pair). These genes are involved in protein degradation, GTPase activity, neuronal loss, and apoptosis. The identified pathways are involved in the cellular processes and neuronal differentiation, which contribute to neuronal loss that is responsible for AD. Furthermore, the most significant SNP (rs12320537) in B4GALNT1 is associated with expression levels of B4GALNT1 in several brain regions. Thus, the identified genes and pathways provide deeper mechanistic insight into the molecular basis of brain atrophy in AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征是大脑中病理变化呈异质性分布。皮质厚度是 AD 的最敏感影像学生物标志物之一，代表结构萎缩。本研究旨在确定与皮质厚度相关的新基因。我们从阿尔茨海默病神经影像学倡议队列中的 919 名受试者的磁共振成像（MRI）扫描中测量了全脑平均皮质厚度，包括 163 名 AD 患者、488 名轻度认知障碍患者和 268 名认知正常参与者。基于基于单核苷酸多态性（SNP）的全基因组关联研究，我们对平均皮质厚度进行了基因关联分析。此外，我们进行了表达数量性状基因座、蛋白质-蛋白质相互作用网络和途径分析，以识别具有生物学功能的信息。我们确定了四个基因（B4GALNT1、RAB44、LOC101927583 和 SLC26A10）、两个途径（细胞周期蛋白依赖性蛋白激酶全酶复合物和核细胞周期蛋白依赖性蛋白激酶全酶复合物）和一个蛋白质-蛋白质相互作用（B4GALNT1 和 GALNT8 对）。这些基因参与蛋白质降解、GTPase 活性、神经元丧失和细胞凋亡。鉴定的途径参与细胞过程和神经元分化，导致 AD 中负责神经元丧失的神经元丧失。此外，B4GALNT1 中最显著的 SNP（rs12320537）与几个脑区 B4GALNT1 的表达水平相关。因此，鉴定的基因和途径为 AD 中大脑萎缩的分子基础提供了更深入的机制见解。
