Molecular Genetics of Anxiety

Abstract

Anxiety is a normal response to a threatening situation. When anxiety is excessive and disturbs daily life and functioning, it can be diagnosed as an anxiety disorder. Anxiety disorders are typical complex disorders that are triggered by environmental factors in genetically susceptible individuals. Genetic variants in many genes have been shown to predispose to anxiety disorders, but the results have been difficult to replicate, most likely due to a small effect size of individual variants. Anxiety is an evolutionarily conserved response, and can therefore be fairly reliably modelled in rodents. Quantitative trait locus mapping and functional genomics and proteomics approaches in mouse models of anxiety have led to the identification of novel genes and pathways that are involved in the regulation of anxiety‐like behaviour. Some of these genes are expected to regulate anxiety in humans as well, and variants in them might predispose to anxiety disorders.

Key Concepts:

  • Anxiety disorders are complex diseases triggered by environmental factors in genetically susceptible individuals.

  • Genetic variants that predispose to anxiety disorders have been identified by candidate gene and genome‐wide association studies.

  • The effect size of the identified susceptibility variants for anxiety disorders seems to be small.

  • Features of human anxiety disorders can be fairly well modelled in animals, and different approaches have revealed novel genes and pathways that regulate anxiety‐like behaviour.

  • Combined information from several approaches, including human and mouse genetics, functional genomics, proteomics, epigenetics and neuroimaging are expected to reveal molecular mechanisms that regulate anxiety.

Keywords: anxiety; linkage; genetic association; candidate gene; gene expression; personality trait; mouse model; stress

Figure 1.

Approaches to study molecular genetics of anxiety.

Figure 2.

A chromosomal map of anxiety‐associated genes and loci. Candidate genes identified in at least two independent association studies with p<.01 for the same SNP and allele are marked in red. Linkage regions found to associate to some anxiety disorder or anxiety‐related personality trait with LOD>3 are marked with green vertical lines. Genes associated to anxiety disorder or anxiety‐related personality trait in a genome‐wide association study are marked with blue colour; PDE4D, MAMDC1 and SNAP25 to neuroticism, TMEM16B and PKP1 to panic disorder, PD, panic disorder. See text for the full‐length names of the genes.

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Burmeister M, McInnis MG and Zollner S (2008) Psychiatric genetics: progress amid controversy. Nature Reviews. Genetics 9: 527–540.

Geschwind DH and Konopka G (2009) Neuroscience in the era of functional genomics and systems biology. Nature 461: 908–915.

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Sipilä, Tessa, and Hovatta, Iiris(Apr 2010) Molecular Genetics of Anxiety. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022422]