A multi-dimensional characterization of anxiety in monozygotic twin pairs reveals susceptibility loci in humans
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The etiology of individual differences in human anxiousness is complex and includes contributions from genetic, epigenetic (i.e., DNA methylation) and environmental factors. Past genomic approaches have been limited in their ability to detect human anxiety-related differences in these factors. To overcome these limitations, we employed both a multi-dimensional characterization method, to select monozygotic twin pairs discordant for anxiety, and whole genome DNA methylation sequencing. This approach revealed 230 anxiety-related differentially methylated loci that were annotated to 183 genes, including several known stress-related genes such as NAV1, IGF2, GNAS, and CRTC1. As an initial validation of these findings, we tested the significance of an overlap of these data with anxiety-related differentially methylated loci that we previously reported from a key neural circuit of anxiety (i.e., the central nucleus of the amygdala) in young monkeys and found a significant overlap (P-value < 0.05) of anxiety-related differentially methylated genes, including GNAS, SYN3, and JAG2. Finally, sequence motif predictions of all the human differentially methylated regions indicated an enrichment of five transcription factor binding motifs, suggesting that DNA methylation may regulate gene expression by mediating transcription factor binding of these transcripts. Together, these data demonstrate environmentally sensitive factors that may underlie the development of human anxiety.
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Clinical genetics have identified various susceptibility genes, including 5-HTT, 5-HT1A receptor, monoamine oxidase A, catechol-O-methyltransferase, phosphodiesterase 4B and BDNF, involved in specific anxiety-relevant phenotypes and/or in the aetiology and maintenance of pathological anxiety in a non-specific or disorder-dependent manner.
“clinical genetics have been able to identify various susceptibility genes, including the 5-HT transporter 5-HTT, 5-HT 1A receptor, monoamine oxidase A, catechol-O-methyltransferase, phosphodiesterase 4B and the brain-derived neurotrophic factor (BDNF) gene, involved in specific anxiety-relevant phenotypes and/or in in the aetiology and maintenance of pathological anxiety in a non-specific or disor”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Alisch et al., 2017
The role of epigenetics as modulatory factors between genetic predisposition and environmental experiences has been increasingly recognized in anxiety.
“The role of epigenetics as modulatory factors between the genetic predisposition and environmental experiences (Kuehner, Bruggeman, Wen, & Yao, 2019) has been increasingly recognized in anxiety (Alisch et al., 2017;Wang, Lou, & Wang, 2019).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Alisch et al., 2017
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- Authors
- Alisch, R. S., Van Hulle, C., Chopra, P., Bhattacharyya, A., Zhang, S.-C., Davidson, R. J., Kalin, N. H., & Goldsmith, H. H.
- Affiliations
- University of Wisconsin–Madison (US)
- Emory University (US)
- Corresponding author
- Alisch, Reid S.
- Goldsmith, H. Hill
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2017-12-11
- Volume
- 7
- Issue
- 12
- Pages
- 1282-1282
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5802687
- OpenAlex
- W2772979793
- Cited by
- 25
- References
- 80
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 6 · 2018: 1
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Hartwell Foundation
- University of Wisconsin-Madison
- National Institute of Mental Health (MH084051, R01 MH59785, P50MH100031, P50MH084051, R01MH059785, R01MH046729)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090256, P30HD003352)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- anxiety, monozygotic twin discordance, DNA methylation, differentially methylated regions, epigenetics, stress-related genes, central amygdala, transcription factor binding motifs, GNAS, insulin-like growth factor II, Jagged2, environmental sensitivity
- MeSH terms
- Adolescent, Amygdala, Anxiety, Anxiety Disorders, Brain Mapping, Female, Humans, Hydrocortisone, Magnetic Resonance Imaging, Male, Twins, Monozygotic, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic
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