Molecular Genetics of Anxiety


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 , PD, panic disorder. See text for the full‐length names of the genes.



American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders: DSM‐IV‐TR, 4th ed. Washington DC: American Psychiatric Association.

Arikian SR and Gorman JM (2001) A review of the diagnosis, pharmacologic treatment, and economic aspects of anxiety disorders. Primary Care Companion to the Journal of Clinical Psychiatry 3: 110–117.

Battaglia M and Ogliari A (2005) Anxiety and panic: from human studies to animal research and back. Neuroscience and Biobehavioral Reviews 29: 169–179.

Battaglia M, Pesenti‐Gritti P, Medland SE et al. (2009) A genetically informed study of the association between childhood separation anxiety, sensitivity to CO(2), panic disorder, and the effect of childhood parental loss. Archives of General Psychiatry 66: 64–71.

Chotai J (1984) On the lod score method in linkage analysis. Annals of Human Genetics 48: 359–378.

Churchill GA, Airey DC, Allayee H et al., Complex Trait Consortium (2004) The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics 36: 1133–1137.

Cloninger CR, Van Eerdewegh P, Goate A et al. (1998) Anxiety proneness linked to epistatic loci in genome scan of human personality traits. American Journal of Medical Genetics 81: 313–317.

Ditzen C, Varadarajulu J, Czibere L et al. (2009) Proteomic‐based genotyping in a mouse model of trait anxiety exposes disease‐relevant pathways. Molecular Psychiatry doi: 10.1038/mp.2008.146 [epub ahead of print].

Domschke K and Dannlowski U (2009) Imaging genetics of anxiety disorders. NeuroImage doi:10.1016/j. neuroimage.2009.11.042 [epub ahead of print].

Donner J, Pirkola S, Silander K et al. (2008) An association analysis of murine anxiety genes in humans implicates novel candidate genes for anxiety disorders. Biological Psychiatry 64: 672–680.

Flint J and Munafo MR (2007) The endophenotype concept in psychiatric genetics. Psychological Medicine 37: 163–180.

Gelernter J, Page GP, Bonvicini K et al. (2003) A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Molecular Psychiatry 8: 71–82.

Goisman RM, Goldenberg I, Vasile RG and Keller MB (1995) Comorbidity of anxiety disorders in a multicenter anxiety study. Comprehensive Psychiatry 36: 303–311.

Hamilton SP, Fyer AJ, Durner M et al. (2003) Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proceedings of the National Academy of Sciences of the USA 100: 2550–2555.

Hettema JM, Neale MC and Kendler KS (2001) A review and meta‐analysis of the genetic epidemiology of anxiety disorders. American Journal of Psychiatry 158: 1568–1578.

Hettema JM, Prescott CA, Myers JM, Neale MC and Kendler KS (2005) The structure of genetic and environmental risk factors for anxiety disorders in men and women. Archives of General Psychiatry 62: 182–189.

Hinds DA, Stuve LL, Nilsen GB et al. (2005) Whole‐genome patterns of common DNA variation in three human populations. Science 307: 1072–1079.

Hohoff C (2009) Anxiety in mice and men: a comparison. Journal of Neural Transmission 116: 679–687.

Hovatta I and Barlow C (2008) Molecular genetics of anxiety in mice and men. Annals of Medicine 40: 92–109.

Hovatta I, Tennant RS, Helton R et al. (2005) Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438: 662–666.

Huang GJ, Shifman S, Valdar W et al. (2009) High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Research 19: 1133.

Kendler KS, Prescott CA, Myers J and Neale MC (2003) The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60: 929.

Kessler RC, Berglund P, Demler O et al. (2005a) Lifetime prevalence and age‐of‐onset distributions of DSM‐IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62: 593–602.

Kessler RC, Chiu WT, Demler O, Merikangas KR and Walters EE (2005b) Prevalence, severity, and comorbidity of 12‐month DSM‐IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry 62: 617–627.

Kromer SA, Kessler MS, Milfay D et al. (2005) Identification of glyoxalase‐I as a protein marker in a mouse model of extremes in trait anxiety. Journal of Neuroscience 25: 4375.

Letwin NE, Kafkafi N, Benjamini Y et al. (2006) Combined application of behavior genetics and microarray analysis to identify regional expression themes and gene‐behavior associations. Journal of Neuroscience 26: 5277.

Mott R and Flint J (2008) Prospects for complex trait analysis in the mouse. Mammalian Genome 19: 306–308.

van den Oord EJ, Kuo PH, Hartmann AM et al. (2008) Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism. Archives of General Psychiatry 65: 1062–1071.

Otowa T, Yoshida E, Sugaya N et al. (2009) Genome‐wide association study of panic disorder in the Japanese population. Journal of Human Genetics 54: 122–126.

Parsons MJ, Grimm CH, Paya‐Cano JL et al. (2008) Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function. Mammalian Genome 19: 552–560.

Pirkola SP, Isometsa E, Suvisaari J et al. (2005) DSM‐IV mood‐, anxiety‐ and alcohol use disorders and their comorbidity in the Finnish general population: results from the Health 2000 Study. Social Psychiatry and Psychiatric Epidemiology 40: 1–10.

Regier DA, Farmer ME, Rae DS et al. (1990) Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA 264: 2511–2518.

Risch N and Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273: 1516–1517.

Schadt EE (2005) Exploiting naturally occurring DNA variation and molecular profiling data to dissect disease and drug response traits. Current Opinion in Biotechnology 16: 647–654.

Segman RH, Shefi N, Goltser‐Dubner T et al. (2005) Peripheral blood mononuclear cell gene expression profiles identify emergent post‐traumatic stress disorder among trauma survivors. Molecular Psychiatry 10: 500–513.

Shifman S, Bhomra A, Smiley S et al. (2007) A whole genome association study of neuroticism using DNA pooling. Molecular Psychiatry 13: 302–312.

Smoller JW, Block SR and Young MM (2009) Genetics of anxiety disorders: the complex road from DSM to DNA. Depression and Anxiety 26: 965–975.

Smoller JW, Gardner‐Schuster E and Misiaszek M (2008) Genetics of anxiety: would the genome recognize the DSM? Depression and Anxiety 25: 368–377.

Su YA, Wu J, Zhang L et al. (2008) Dysregulated mitochondrial genes and networks with drug targets in postmortem brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria‐focused cDNA microarrays. International Journal of Biological Sciences 4: 223–235.

Terracciano A, Sanna S, Uda M et al. (2008) Genome‐wide association scan for five major dimensions of personality. Molecular Psychiatry doi: 10.1038/mp.2008.113 [epub ahead of print].

Thorgeirsson TE, Oskarsson H, Desnica N et al. (2003) Anxiety with panic disorder linked to chromosome 9q in Iceland. American Journal of Human Genetics 72: 1221–1230.

Tsankova N, Renthal W, Kumar A and Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nature Reviews. Neuroscience 8: 355–367.

Weaver ICG, Cervoni N, Champagne FA et al. (2004) Epigenetic programming by maternal behavior. Nature Neuroscience 7: 847–854.

Williams R, Lim JE, Harr B et al. (2009) A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety‐like behavior. PLoS One 4: 4649.

Yalcin B, Willis‐Owen SAG, Fullerton J et al. (2004) Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nature Genetics 36: 1197–1202.

Yehuda R, Cai G, Golier JA et al. (2009) Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biological Psychiatry 66: 708–711.

Further Reading

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. [doi: 10.1002/9780470015902.a0022422]