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Methylome-wide association study of anxiety disorders.

Publication ,  Journal Article
Hettema, JM; van den Oord, EJCG; Zhao, M; Xie, LY; Copeland, WE; Penninx, BWJH; Aberg, KA; Clark, SL
Published in: Mol Psychiatry
August 2023

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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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

August 2023

Volume

28

Issue

8

Start / End Page

3484 / 3492

Location

England

Related Subject Headings

  • Schizophrenia
  • Psychiatry
  • Mice
  • Humans
  • Genome-Wide Association Study
  • Epigenome
  • DNA Methylation
  • CpG Islands
  • Anxiety Disorders
  • Animals
 

Citation

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ICMJE
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Hettema, J. M., van den Oord, E. J. C. G., Zhao, M., Xie, L. Y., Copeland, W. E., Penninx, B. W. J. H., … Clark, S. L. (2023). Methylome-wide association study of anxiety disorders. Mol Psychiatry, 28(8), 3484–3492. https://doi.org/10.1038/s41380-023-02205-w
Hettema, John M., Edwin J. C. G. van den Oord, Min Zhao, Lin Y. Xie, William E. Copeland, Brenda W. J. H. Penninx, Karolina A. Aberg, and Shaunna L. Clark. “Methylome-wide association study of anxiety disorders.Mol Psychiatry 28, no. 8 (August 2023): 3484–92. https://doi.org/10.1038/s41380-023-02205-w.
Hettema JM, van den Oord EJCG, Zhao M, Xie LY, Copeland WE, Penninx BWJH, et al. Methylome-wide association study of anxiety disorders. Mol Psychiatry. 2023 Aug;28(8):3484–92.
Hettema, John M., et al. “Methylome-wide association study of anxiety disorders.Mol Psychiatry, vol. 28, no. 8, Aug. 2023, pp. 3484–92. Pubmed, doi:10.1038/s41380-023-02205-w.
Hettema JM, van den Oord EJCG, Zhao M, Xie LY, Copeland WE, Penninx BWJH, Aberg KA, Clark SL. Methylome-wide association study of anxiety disorders. Mol Psychiatry. 2023 Aug;28(8):3484–3492.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

August 2023

Volume

28

Issue

8

Start / End Page

3484 / 3492

Location

England

Related Subject Headings

  • Schizophrenia
  • Psychiatry
  • Mice
  • Humans
  • Genome-Wide Association Study
  • Epigenome
  • DNA Methylation
  • CpG Islands
  • Anxiety Disorders
  • Animals