期刊
MOLECULAR PSYCHIATRY
卷 27, 期 11, 页码 4432-4445出版社
SPRINGERNATURE
DOI: 10.1038/s41380-022-01800-7
关键词
-
资金
- National Key Research and Development Program of China [2018YFC1314301, 2017YFA0604401, 2017YFA0504102]
- National Natural Science Foundation of China [82001797, 82030053, 32070675, 81801687]
- Tianjin Applied Basic Research Diversified Investment Foundation [21JCYBJC01360]
- Tianjin Health Technology Project [TJWJ2021QN002]
- Science&Technology Development Fund of Tianjin Education Commission for Higher Education [2019KJ195]
- Natural Science Foundation of Tianjin City [19JCJQJC63600, 18JCJQJC48200]
- Tianjin Key Medical Discipline (Specialty) Construction Project [TJYXZDXK-001A]
- Horizon 2020 [695313]
- National Institute of Health (NIH) [R01DA049238, ANR-18-NEUR00002-01ADORe]
- Human Brain Project SGA3 [945539]
- Chinese National High-end Foreign Expert Recruitment Plan
- ANR [AAPG2019-GeBra]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense ) [W81XWH-12-2-0012]
- National Institute on Aging
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Cogstate
- Elan Pharmaceuticals, Inc.
- Eisai Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd.
- Genentech, Inc.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC
- Johnson & Johnson Pharmaceutical Research & Development LLC
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- National Institute of Biomedical Imaging and Bioengineering
This study integrates cross-omics analysis with genome editing, overexpression, and causality inference to identify the causal relationships between SNPs, DNA methylation, and gene expression and human hippocampal volume. The findings reveal a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume and provide insights for the design of prevention and treatment strategies for hippocampal impairment.
Human hippocampal volume has been separately associated with single nucleotide polymorphisms (SNPs), DNA methylation and gene expression, but their causal relationships remain largely unknown. Here, we aimed at identifying the causal relationships of SNPs, DNA methylation, and gene expression that are associated with hippocampal volume by integrating cross-omics analyses with genome editing, overexpression and causality inference. Based on structural neuroimaging data and blood-derived genome, transcriptome and methylome data, we prioritized a possibly causal association across multiple molecular phenotypes: rs1053218 mutation leads to cg26741686 hypermethylation, thus leads to overactivation of the associated ANKRD37 gene expression in blood, a gene involving hypoxia, which may result in the reduction of human hippocampal volume. The possibly causal relationships from rs1053218 to cg26741686 methylation to ANKRD37 expression obtained from peripheral blood were replicated in human hippocampal tissue. To confirm causality, we performed CRISPR-based genome and epigenome-editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and overexpressed ANKRD37 in mouse hippocampus. These in-vitro and in-vivo experiments confirmed that rs1053218 mutation caused cg26741686 hypermethylation and ANKRD37 overexpression, and cg26741686 hypermethylation favored ANKRD37 overexpression, and ANKRD37 overexpression reduced hippocampal volume. The pairwise relationships of rs1053218 with hippocampal volume, rs1053218 with cg26741686 methylation, cg26741686 methylation with ANKRD37 expression, and ANKRD37 expression with hippocampal volume could be replicated in an independent healthy young (n = 443) dataset and observed in elderly people (n = 194), and were more significant in patients with late-onset Alzheimer's disease (n = 76). This study revealed a novel causal molecular association mechanism of ANKRD37 with human hippocampal volume, which may facilitate the design of prevention and treatment strategies for hippocampal impairment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据