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A causal association of ANKRD37 with human hippocampal volume

Molecular Psychiatry volume 27, pages 4432–4445 (2022)Cite this article

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Abstract

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.

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Fig. 1: A schematic summary of the study design.
Fig. 2: Identifying possibly casual S → M → E → H associations in blood and hippocampal tissues.
Fig. 3: Validation of S → M, S → E and M → E causal effects in mouse neural stem cell (NSC).
Fig. 4: Validation of E → H causal association in mice hippocampus.
Fig. 5: Pairwise replication of the S → M → E → H associations of ANKRD37 in HYC and pairwise comparisons in different populations.

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Code availability

Custom code that supports the findings of this study is available from the corresponding author upon request.

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Acknowledgements

This work was partly supported by the National Key Research and Development Program of China (Grant No. 2018YFC1314301), National Natural Science Foundation of China (Grant No. 82001797), Tianjin Applied Basic Research Diversified Investment Foundation (Grant No. 21JCYBJC01360), Tianjin Health Technology Project (Grant No. TJWJ2021QN002), Science&Technology Development Fund of Tianjin Education Commission for Higher Education (2019KJ195), National Key Research and Development Program of China (Grant No. 2017YFA0604401 and 2017YFA0504102), National Natural Science Foundation of China (Grant No. 82030053, 32070675 and 81801687), Natural Science Foundation of Tianjin City (Grant No. 19JCJQJC63600 for MJL and 18JCJQJC48200 for XW), Tianjin Key Medical Discipline (Specialty) Construction Project (Grant No. TJYXZDXK-001A). Further support was received by GS from the Horizon 2020 funded ERC Advanced Grant “STRATIFY” (Brain network-based stratification of reinforcement-related disorders) (695313), the National Institute of Health (NIH) (R01DA049238, A decentralized macro and micro gene-by-environment interaction analysis of substance use behavior and its brain biomarkers), the Human Brain Project (SGA3; 945539), and the Chinese National High-end Foreign Expert Recruitment Plan. Further support was provided by grants from the ANR (AAPG2019-GeBra), the Eranet Neuron (ANR-18-NEUR00002-01- ADORe). Healthy elderly controls and LOAD cases data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company 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; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Author information

Author notes

  1. These authors contributed equally: Jiayuan Xu, Xianyou Xia, Qiaojun Li, Yan Dou.

  2. A list of members and their affiliations of IMAGEN Consortia appears in the Supplementary Information.

Authors and Affiliations

  1. Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, 300052, PR China

    Jiayuan Xu, Yan Dou, Xinjun Suo, Zuhao Sun, Nana Liu, Xiaodi Sun, Wen Qin & Chunshui Yu

  2. Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, 300070, PR China

    Xianyou Xia, Yating Han & Xudong Wu

  3. College of Information Engineering, Tianjin University of Commerce, Tianjin, 300052, PR China

    Qiaojun Li

  4. Department of Pharmacology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, PR China

    Yukun He, Shijie Zhang & Mulin Jun Li

  5. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, 68159, Mannheim, Germany

    Tobias Banaschewski, Frauke Nees, Sarah Hohmann & Frauke Nees

  6. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, Germany

    Herta Flor, Frauke Nees & Herta Flor

  7. Department of Psychology, School of Social Sciences, University of Mannheim, 68131, Mannheim, Germany

    Herta Flor & Herta Flor

  8. NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France

    Antoine Grigis

  9. Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK

    Penny Gowland

  10. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charitéplatz 1, Berlin, Germany

    Andreas Heinz & Henrik Walter

  11. Physikalisch-Technische Bundesanstalt (PTB), Abbestr. 2 - 12, Berlin, Germany

    Rüdiger Brühl

  12. Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, INSERM U1299 “Developmental trajectories & psychiatry”; Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli, Gif-sur-Yvette, France

    Jean-Luc Martinot

  13. Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, INSERM U1299 “Developmental trajectories & psychiatry”; Ecole Normale supérieure Paris-Saclay, CNRS, Centre Borelli; Gif-sur-Yvette; and Etablissement Public de Santé (EPS) Barthélemy Durand, 91700, Sainte-Geneviève-des-Bois, France

    Eric Artiges

  14. Institute of Medical Psychology and Medical Sociology, University Medical Center Schleswig-Holstein, Kiel University, Kiel, Germany

    Frauke Nees

  15. Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, M6A 2E1, Canada

    Tomáš Paus

  16. Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Centre Göttingen, von-Siebold-Str. 5, 37075, Göttingen, Germany

    Luise Poustka

  17. Centre for PanorOmic Sciences-Genomics and Bioinformatics Cores, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 999077, P.R. China

    Pak Chung Sham

  18. Centre for Population Neuroscience and Stratified Medicine (PONS), Institute for Science and Technology of Brain-inspired Intelligence 20 (ISTBI), Fudan University, Shanghai, P.R. China

    Gunter Schumann & Gunter Schumann

  19. PONS Centre, Department of Psychiatry and Psychotherapy, CCM, Charite Universitaetsmedizin Berlin, Berlin, Germany

    Gunter Schumann & Gunter Schumann

  20. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China

    Xudong Wu

  21. Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China

    Mulin Jun Li

  22. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, PR China

    Chunshui Yu

  23. Departments of Psychiatry and Neuroscience, Faculty of Medicine and Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada

    Tomáš Paus

  24. Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, Canada

    Tomáš Paus

Authors
  1. Jiayuan Xu
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  2. Xianyou Xia
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  3. Qiaojun Li
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  4. Yan Dou
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  5. Xinjun Suo
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  6. Zuhao Sun
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  28. Xudong Wu
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Consortia

for the Alzheimer’s Disease Neuroimaging Initiative

IMAGEN Consortia

  • Tobias Banaschewski
  • , Frauke Nees
  • , Sarah Hohmann
  • , Herta Flor
  • , Antoine Grigis
  • , Penny Gowland
  • , Andreas Heinz
  • , Henrik Walter
  • , Rüdiger Brühl
  • , Jean-Luc Martinot
  • , Eric Artiges
  • , Tomáš Paus
  • , Luise Poustka
  •  & Gunter Schumann

Contributions

JX, MJL, XW, and CY designed the study. JX, XX, YD, MJL, XW, and CY wrote the manuscript. JX, QL, XX and ZS analysed the data. All authors critically reviewed the manuscript. XS, NL, YH, XS, YH, WQ and SZ were the principal investigators. TB, HF, AG, PG, AH, RB, JM, EA, FN, TP, LP, SH, HW, PS and GS acquired the data.

Corresponding authors

Correspondence to Xudong Wu, Mulin Jun Li or Chunshui Yu.

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Xu, J., Xia, X., Li, Q. et al. A causal association of ANKRD37 with human hippocampal volume. Mol Psychiatry 27, 4432–4445 (2022). https://doi.org/10.1038/s41380-022-01800-7

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