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A causal association of ANKRD37 with human hippocampal volume

Xu, Jiayuan; Xia, Xianyou; Li, Qiaojun; Dou, Yan; Suo, Xinjun; Liu, Nana; Han, Yating; Sun, Xiaodi; He, Yukun; Qin, Wen; Zhang, Shijie; Banaschewski, Tobias; Flor, Herta; Grigis, Antoine; Gowland, Penny; Heinz, Andreas; Brühl, Rüdiger; Martinot, Jean Luc; Artiges, Eric; Nees, Frauke; Paus, Tomáš; Poustka, Luise; Hohmann, Sarah; Walter, Henrik; Sham, Pak Chung; Schumann, Gunter; Wu, Xudong; Li, Mulin Jun; Yu, Chunshui; Consortium, Alzheimer’s Disease Neuroimaging Initiative; Consortium, IMAGEN

A causal association of ANKRD37 with human hippocampal volume Thumbnail


Jiayuan Xu

Xianyou Xia

Qiaojun Li

Yan Dou

Xinjun Suo

Nana Liu

Yating Han

Xiaodi Sun

Yukun He

Wen Qin

Shijie Zhang

Tobias Banaschewski

Herta Flor

Antoine Grigis

Andreas Heinz

Rüdiger Brühl

Jean Luc Martinot

Eric Artiges

Frauke Nees

Tomáš Paus

Luise Poustka

Sarah Hohmann

Henrik Walter

Pak Chung Sham

Gunter Schumann

Xudong Wu

Mulin Jun Li

Chunshui Yu

Alzheimer’s Disease Neuroimaging Initiative Consortium

IMAGEN Consortium


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.


Xu, J., Xia, X., Li, Q., Dou, Y., Suo, X., Liu, N., …Consortium, I. (2022). A causal association of ANKRD37 with human hippocampal volume. Molecular Psychiatry, 27, 4432-4445.

Journal Article Type Article
Acceptance Date Sep 12, 2022
Online Publication Date Oct 4, 2022
Publication Date 2022-11
Deposit Date Sep 2, 2022
Publicly Available Date Apr 5, 2023
Journal Molecular Psychiatry
Print ISSN 1359-4184
Electronic ISSN 1476-5578
Publisher Springer Science and Business Media LLC
Peer Reviewed Peer Reviewed
Volume 27
Pages 4432-4445
Keywords Cellular and Molecular Neuroscience; Psychiatry and Mental health; Molecular Biology
Public URL
Publisher URL
Additional Information Authors on behalf of Alzheimer's Disease Neuroimaging Initiative and IMAGEN Consortia.


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