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人类阿尔茨海默病、衰老和长寿的遗传网络。

Genetic Networks of Alzheimer's Disease, Aging, and Longevity in Humans.

机构信息

Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA.

出版信息

Int J Mol Sci. 2023 Mar 8;24(6):5178. doi: 10.3390/ijms24065178.

Abstract

Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer's disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of -value < 1.00 × 10 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of < 1.00 × 10, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression ( = 4.05 × 10) including ApoE, SOD2, TP53, and TGFB1 ( = 2.84 × 10); protein metabolism and SUMOylation, including E3 ligases and target proteins ( = 1.08 × 10); ERBB4 signal transduction ( = 2.69 × 10); the immune system, including IL-3 and IL-13 ( = 3.83 × 10); programmed cell death ( = 4.36 × 10); and platelet degranulation ( = 8.16 × 10), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 ( = 7.64 × 10), plasma lipoprotein assembly, remodeling and clearance ( < 4.02 × 10), and the metabolism of fat-soluble vitamins ( = 1.96 × 10). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.

摘要

人类基因组分析和全基因组关联研究 (GWAS) 已经确定了早发性和晚发性阿尔茨海默病 (AD 基因) 的风险因素基因。尽管衰老和长寿的遗传学已经得到了广泛的研究,但以前的研究主要集中在一组已被证明与 AD 有关或具有 AD 风险的特定基因上。因此,AD、衰老和长寿之间的基因联系尚不清楚。在这里,我们通过使用 Reactome 的基因集富集分析来确定 AD 背景下的衰老和长寿的遗传相互作用网络 (称为途径),该分析交叉引用了 100 多个生物信息学数据库,允许通过广泛的基因网络来解释基因集的生物学功能。我们使用数据库提取了 356 个 AD 基因、307 个与衰老相关 (AR) 基因和 357 个长寿基因的列表,通过 -值 < 1.00 × 10 的阈值来验证途径。AR 和长寿基因与 AD 基因共享广泛的生物学途径。在 < 1.00 × 10 的阈值内,AR 基因确定了 261 个途径,其中 26 个途径 (AR 基因途径的 10%)是通过 AD 和 AR 基因之间的重叠基因进一步确定的。重叠途径包括基因表达 ( = 4.05 × 10),包括 ApoE、SOD2、TP53 和 TGFB1 ( = 2.84 × 10);蛋白质代谢和 SUMOylation,包括 E3 连接酶和靶蛋白 ( = 1.08 × 10);ERBB4 信号转导 ( = 2.69 × 10);免疫系统,包括 IL-3 和 IL-13 ( = 3.83 × 10);程序性细胞死亡 ( = 4.36 × 10);血小板脱颗粒 ( = 8.16 × 10) 等。在阈值内,长寿基因确定了 49 个途径,其中 12 个途径 (长寿基因途径的 24%)是通过 AD 和长寿基因之间的重叠基因进一步确定的。它们包括免疫系统,包括 IL-3 和 IL-13 ( = 7.64 × 10)、血浆脂蛋白组装、重塑和清除 ( < 4.02 × 10) 和脂溶性维生素的代谢 ( = 1.96 × 10)。因此,这项研究为衰老、长寿和 AD 的共享遗传特征提供了统计意义上的支持。我们讨论了这些途径中涉及的重要基因,包括 TP53、FOXO、SUMOylation、IL4、IL6、APOE 和 CEP,表明映射基因网络途径为 AD 和健康衰老的进一步医学研究提供了有用的基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3079/10049434/f95d327635be/ijms-24-05178-g001.jpg

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