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The Successive Alleys Test of Anxiety in Mice and Rats
Published on: June 17, 2013
Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder
Abigail R Ter Kuile1,2,3, Brittany L Mitchell4,5, Sang Hyuck Lee1
1Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Molecular Psychiatry
|June 29, 2026
Summary
Genetic studies show anxiety disorders and depression share many genes. While some genetic differences exist between fear-based anxiety and generalized anxiety disorder, a common genetic liability underlies internalizing disorders.
Area of Science:
- Psychiatry
- Genetics
- Internalizing Disorders
Background:
- Twin studies indicate substantial genetic overlap between anxiety disorders and depression, forming the internalizing spectrum.
- Emerging evidence suggests genetic specificity for fear-based anxiety disorders, distinct from generalized anxiety and depression (distress).
- Limited phenotyping in prior genome-wide association studies (GWAS) often restricted analyses to broad "any anxiety" diagnoses.
Purpose of the Study:
- To conduct GWAS meta-analyses to identify genetic differences between fear-based anxiety disorders and generalized anxiety disorder (GAD).
- To explore the impact of control group selection (phenotype-specific vs. broad screening) on genetic correlation estimates.
- To investigate the genetic correlations of fear and GAD with various complex traits, including depression, cognitive ability, and other psychiatric disorders.
Main Methods:
- Performed GWAS meta-analyses for fear-based anxiety disorders and GAD across three datasets, using both brief and detailed diagnostic measures.
- Examined two control group criteria: phenotype-specific (fear/GAD) and broader anxiety/depression screening.
- Calculated genetic correlations between fear and GAD, and between these disorders and other complex traits.
Main Results:
- Identified significant genome-wide loci and gene-level associations for both fear (1 locus, 3 genes) and GAD (4 loci, 3 genes).
- The genetic correlation between fear and GAD was significantly different from unity only under specific conditions (excluding a depression-enriched dataset and using phenotype-specific controls; rg = 0.87).
- Fear and GAD showed similar genetic correlations with most traits, including depression. However, fear showed stronger correlations with cognitive ability and coronary artery disease, while GAD showed stronger correlations with bipolar disorder I, anorexia nervosa, and neuroticism.
Conclusions:
- Findings partially support a genetic distinction between distress and fear-based anxiety.
- A significant overarching genetic liability to internalizing psychopathology appears to drive comorbidity across anxiety disorders and depression.
- Future research should consider detailed phenotyping and appropriate control selection in GWAS to better elucidate the genetic architecture of internalizing disorders.
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