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Methylome-wide association study of anxiety disorders

Molecular Psychiatry volume 28, pages 3484–3492 (2023)Cite this article

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Abstract

Anxiety Disorders (ANX) such as panic disorder, generalized anxiety disorder, and phobias, are highly prevalent conditions that are moderately heritable. Evidence suggests that DNA methylation may play a role, as it is involved in critical adaptations to changing environments. Applying an enrichment-based sequencing approach covering nearly 28 million autosomal CpG sites, we conducted a methylome-wide association study (MWAS) of lifetime ANX in 1132 participants (618 cases/514 controls) from the Netherlands Study of Depression and Anxiety. Using epigenomic deconvolution, we performed MWAS for the main cell types in blood: granulocytes, T-cells, B-cells and monocytes. Cell-type specific analyses identified 280 and 82 methylome-wide significant associations (q-value < 0.1) in monocytes and granulocytes, respectively. Our top finding in monocytes was located in ZNF823 on chromosome 19 (p = 1.38 × 10−10) previously associated with schizophrenia. We observed significant overlap (p < 1 × 10−06) with the same direction of effect in monocytes (210 sites), T-cells (135 sites), and B-cells (727 sites) between this Discovery MWAS signal and a comparable replication dataset from the Great Smoky Mountains Study (N = 433). Overlapping Discovery-Replication MWAS signal was enriched for findings from published GWAS of ANX, major depression, and post-traumatic stress disorder. In monocytes, two specific sites in the FZR1 gene showed significant replication after Bonferroni correction with an additional 15 nominally replicated sites in monocytes and 4 in T-cells. FZR1 regulates neurogenesis in the hippocampus, and its knockout leads to impairments in associative fear memory and long-term potentiation in mice. In the largest and most extensive methylome-wide study of ANX, we identified replicable methylation sites located in genes of potential relevance for brain mechanisms of psychiatric conditions.

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Fig. 1: Quantile-Quantile plot for discovery MWAS in whole blood and cell-type specific MWAS.
Fig. 2: Clustering significantly enriched pathways for B-cells.

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Data availability

Full summary results are available upon request from the corresponding author. NESDA and GSMS data are available through an application and approval process through their corresponding institutions.

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Acknowledgements

This study was supported by the National Institutes of Health (R01MH099110 & 1R01MH104576 to E.J.C.G., 5R01MH113665 to J.M.H, R01MH109525 to K.A. and 1R01AA026057 to S.L.C.). The funding sources had no role in the study design, writing of the report or decision to submit the article for publication. The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum).

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Authors and Affiliations

  1. Department of Psychiatry & Behavioral Sciences, Texas A&M University, College Station, TX, USA

    John M. Hettema & Shaunna L. Clark

  2. Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, Richmond, VA, USA

    Edwin J. C. G. van den Oord, Min Zhao, Lin Y. Xie & Karolina A. Aberg

  3. Department of Psychiatry, University of Vermont, Burlington, VA, USA

    William E. Copeland

  4. Department of Psychiatry, VU University Medical Center / GGZ inGeest, Amsterdam, 1081 HV, the Netherlands

    Brenda W. J. H. Penninx

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  1. John M. Hettema
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Hettema, J.M., van den Oord, E.J.C.G., Zhao, M. et al. Methylome-wide association study of anxiety disorders. Mol Psychiatry 28, 3484–3492 (2023). https://doi.org/10.1038/s41380-023-02205-w

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