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Genetics of Anxiety Disorders

  • Sandra M. MeierEmail author
  • Jürgen Deckert
Genetic Disorders (F Goes, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetic Disorders

Abstract

Purpose of Review

Anxiety disorders are among the most common mental disorders with a lifetime prevalence of over 20%. Clinically, anxiety is not thought of as a homogenous disorder, but is subclassified in generalized, panic, and phobic anxiety disorder. Anxiety disorders are moderately heritable. This review will explore recent genetic and epigenetic approaches to anxiety disorders explaining differential susceptibility risk.

Recent Findings

A substantial portion of the variance in susceptibility risk can be explained by differential inherited and acquired genetic and epigenetic risk. Available data suggest that anxiety disorders are highly complex and polygenic. Despite the substantial progress in genetic research over the last decade, only few risk loci for anxiety disorders have been identified so far.

Summary

This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. We discuss prospects for clinical translation of genetic findings and future directions for research.

Keywords

Anxiety Genetic Epigenetics GWAS 

Notes

Funding

The work described in this article has been generously funded by the Canada Research Chairs Program and the DFG-funded Comprehensive Research Center TR 58 on Fear, Anxiety and Anxiety Disorders (Project Z02).

Compliance with Ethical Standards

Conflict of Interest

Sandra M. Meier declares no conflict of interest.

Jürgen Deckert reports grants from P1Vital, Biovariance, DFG, and BMBF.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG, Gruber MJ, et al. Prevalence, persistence, and sociodemographic correlates of DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Arch Gen Psychiatry. 2012;69:372–80.CrossRefGoogle Scholar
  2. 2.
    Baxter AJ, Vos T, Scott KM, Ferrari AJ, Whiteford HA. The global burden of anxiety disorders in 2010. Psychol Med. 2014;44:2363–74.CrossRefGoogle Scholar
  3. 3.
    Gottschalk MG, Domschke K. Novel developments in genetic and epigenetic mechanisms of anxiety. Curr Opin Psychiatry. 2016;29:32–8.CrossRefGoogle Scholar
  4. 4.
    Freud S. On the right to separate from neurasthenia a definite symptom-complex as “anxiety neurosis”. Selected Papers on Hysteria and Other Psychoneuroses 1895.Google Scholar
  5. 5.
    Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158:1568–78.CrossRefGoogle Scholar
  6. 6.
    Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry. 2005;62:182–9.CrossRefGoogle Scholar
  7. 7.
    Smoller JW, Gardner-Schuster E, Covino J. The genetic basis of panic and phobic anxiety disorders. Am J Med Genet C Semin Med Genet. 2008;148C:118–26.CrossRefGoogle Scholar
  8. 8.
    Tambs K, Czajkowsky N, Roysamb E, Neale MC, Reichborn-Kjennerud T, Aggen SH, et al. Structure of genetic and environmental risk factors for dimensional representations of DSM-IV anxiety disorders. Br J Psychiatry. 2009;195:301–7.CrossRefGoogle Scholar
  9. 9.
    Maron E, Hettema JM, Shlik J. Advances in molecular genetics of panic disorder. Mol Psychiatry. 2010;15:681–701.CrossRefGoogle Scholar
  10. 10.
    Wray NR, James MR, Gordon SD, Dumenil T, Ryan L, Coventry WL, et al. Accurate, large-scale genotyping of 5HTTLPR and flanking single nucleotide polymorphisms in an association study of depression, anxiety, and personality measures. Biol Psychiatry. 2009;66:468–76.CrossRefGoogle Scholar
  11. 11.
    Knuts I, Esquivel G, Kenis G, Overbeek T, Leibold N, Goossens L, et al. Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia. Eur Neuropsychopharmacol. 2014;24:1222–8.CrossRefGoogle Scholar
  12. 12.
    Eley TC, Hudson JL, Creswell C, Tropeano M, Lester KJ, Cooper P, et al. Therapygenetics: the 5HTTLPR and response to psychological therapy. Mol Psychiatry. 2012;17:236–7.CrossRefGoogle Scholar
  13. 13.
    Lester KJ, Roberts S, Keers R, Coleman JR, Breen G, Wong CC, et al. Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders. Br J Psychiatry. 2016;208:182–8.CrossRefGoogle Scholar
  14. 14.
    Stein MB, Keshaviah A, Haddad SA, Van Ameringen M, Simon NM, Pollack MH, et al. Influence of RGS2 on sertraline treatment for social anxiety disorder. Neuropsychopharmacology. 2014;39:1340–6.CrossRefGoogle Scholar
  15. 15.
    Howe AS, Buttenschon HN, Bani-Fatemi A, Maron E, Otowa T, Erhardt A, et al. Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways. Mol Psychiatry. 2016;21:665–79.CrossRefGoogle Scholar
  16. 16.
    Narasimhan S, Aquino TD, Multani PK, Rickels K, Lohoff FW. Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder. Psychiatry Res. 2012;198:112–5.CrossRefGoogle Scholar
  17. 17.
    Andersson E, Ruck C, Lavebratt C, Hedman E, Schalling M, Lindefors N, et al. Genetic polymorphisms in monoamine systems and outcome of cognitive behavior therapy for social anxiety disorder. PLoS One. 2013;8:e79015.CrossRefGoogle Scholar
  18. 18.
    Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet. 1999;8:621–4.CrossRefGoogle Scholar
  19. 19.
    Reif A, Richter J, Straube B, Hofler M, Lueken U, Gloster AT, et al. MAOA and mechanisms of panic disorder revisited: from bench to molecular psychotherapy. Mol Psychiatry. 2014;19:122–8.CrossRefGoogle Scholar
  20. 20.
    Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM, Rawlins JN, et al. Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat Genet. 2004;36:1197–202.CrossRefGoogle Scholar
  21. 21.
    Hohoff C, Weber H, Richter J, Domschke K, Zwanzger PM, Ohrmann P, et al. RGS2 genetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety. Am J Med Genet B Neuropsychiatr Genet. 2015;168B:211–22.CrossRefGoogle Scholar
  22. 22.
    Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K, et al. Genome-wide association study of panic disorder in the Japanese population. J Hum Genet. 2009;54:122–6.CrossRefGoogle Scholar
  23. 23.
    Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, et al. Replication of a genome-wide association study of panic disorder in a Japanese population. J Hum Genet. 2010;55:91–6.CrossRefGoogle Scholar
  24. 24.
    Otowa T, Kawamura Y, Nishida N, Sugaya N, Koike A, Yoshida E, et al. Meta-analysis of genome-wide association studies for panic disorder in the Japanese population. Transl Psychiatry. 2012;2:e186.CrossRefGoogle Scholar
  25. 25.
    Erhardt A, Czibere L, Roeske D, Lucae S, Unschuld PG, Ripke S, et al. TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies. Mol Psychiatry. 2011;16:647–63.CrossRefGoogle Scholar
  26. 26.
    • Erhardt A, Akula N, Schumacher J, Czamara D, Karbalai N, Muller-Myhsok B, et al. Replication and meta-analysis of TMEM132D gene variants in panic disorder. Transl Psychiatry. 2012;2:e156 This study provides the first genome-wide association finding in panic disorder.CrossRefGoogle Scholar
  27. 27.
    Haaker J, Lonsdorf TB, Raczka KA, Mechias ML, Gartmann N, Kalisch R. Higher anxiety and larger amygdala volumes in carriers of a TMEM132D risk variant for panic disorder. Transl Psychiatry. 2014;4:e357.CrossRefGoogle Scholar
  28. 28.
    Trzaskowski M, Eley TC, Davis OS, Doherty SJ, Hanscombe KB, Meaburn EL, et al. First genome-wide association study on anxiety-related behaviours in childhood. PLoS One. 2013;8:e58676.CrossRefGoogle Scholar
  29. 29.
    Walter S, Glymour MM, Koenen K, Liang L, Tchetgen Tchetgen EJ, Cornelis M, et al. Performance of polygenic scores for predicting phobic anxiety. PLoS One. 2013;8:e80326.CrossRefGoogle Scholar
  30. 30.
    Dunn EC, Sofer T, Gallo LC, Gogarten SM, Kerr KF, Chen CY, et al. Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos. Am J Med Genet B Neuropsychiatr Genet. 2017;174:132–43.CrossRefGoogle Scholar
  31. 31.
    Stein MB, Chen CY, Jain S, Jensen KP, He F, Heeringa SG, et al. Genetic risk variants for social anxiety. Am J Med Genet B Neuropsychiatr Genet. 2017;174:120–31.CrossRefGoogle Scholar
  32. 32.
    Davies MN, Verdi S, Burri A, Trzaskowski M, Lee M, Hettema JM, et al. Generalised anxiety disorder—a twin study of genetic architecture, genome-wide association and differential gene expression. PLoS One. 2015;10:e0134865.CrossRefGoogle Scholar
  33. 33.
    • Deckert J, Weber H, Villmann C, Lonsdorf TB, Richter J, Andreatta M, et al. GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder. Mol Psychiatry. 2017;22:1431–9 This study describes a genome-wide significant association for a dimensional anxiety trait.CrossRefGoogle Scholar
  34. 34.
    Otowa T, Maher BS, Aggen SH, McClay JL, van den Oord EJ, Hettema JM. Genome-wide and gene-based association studies of anxiety disorders in European and African American samples. PLoS One. 2014;9:e112559.CrossRefGoogle Scholar
  35. 35.
    •• Otowa T, Hek K, Lee M, Byrne EM, Mirza SS, Nivard MG, et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol Psychiatry. 2016;21:1391–9 This first large-scale metanalysis of anxiety disorders of the ANGST consortium describes two genome-wide findings.CrossRefGoogle Scholar
  36. 36.
    Okbay A, Baselmans BM, De Neve JE, Turley P, Nivard MG, Fontana MA, et al. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses. Nat Genet. 2016;48:624–33.CrossRefGoogle Scholar
  37. 37.
    •• Purves KL, Coleman JRI, Rayner C, Hettema JM, Deckert J, McIntosh AM, et al. The common genetic architecture of anxiety disorders. bioRxiv 203844;  https://doi.org/10.1101/203844 This preprint manuscript describes results from the UKBiobank cohort on generalized anxiety disorder at a categorical and a dimensional trait level.
  38. 38.
    Meier S, Trontti K, Als TD, Laine M, Pedersen MG, Byberg-Grauholm J, et al. Genome-wide association study of anxiety and stress-related disorders in the iPSYCH cohort. bioRxiv 263855;  https://doi.org/10.1101/263855.
  39. 39.
    Zhang HT, Huang Y, Masood A, Stolinski LR, Li Y, Zhang L, et al. Anxiogenic-like behavioral phenotype of mice deficient in phosphodiesterase 4B (PDE4B). Neuropsychopharmacology. 2008;33:1611–23.CrossRefGoogle Scholar
  40. 40.
    Coleman JR, Lester KJ, Keers R, Roberts S, Curtis C, Arendt K, et al. Genome-wide association study of response to cognitive-behavioural therapy in children with anxiety disorders. Br J Psychiatry. 2016;209:236–43.CrossRefGoogle Scholar
  41. 41.
    Huang B, Jiang C, Zhang R. Epigenetics: the language of the cell? Epigenomics. 2014;6:73–88.CrossRefGoogle Scholar
  42. 42.
    Schiele MA, Domschke K. Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders. Genes Brain Behav. 2018;17:e12423.CrossRefGoogle Scholar
  43. 43.
    Shimada-Sugimoto M, Otowa T, Miyagawa T, Umekage T, Kawamura Y, Bundo M, et al. Epigenome-wide association study of DNA methylation in panic disorder. Clin Epigenetics. 2017;9:6.CrossRefGoogle Scholar
  44. 44.
    Murphy TM, O'Donovan A, Mullins N, O'Farrelly C, McCann A, Malone K. Anxiety is associated with higher levels of global DNA methylation and altered expression of epigenetic and interleukin-6 genes. Psychiatr Genet. 2015;25:71–8.CrossRefGoogle Scholar
  45. 45.
    Emeny RT, Baumert J, Zannas AS, Kunze S, Wahl S, Iurato S, et al. Anxiety associated increased CpG methylation in the promoter of Asb1: a translational approach evidenced by epidemiological and clinical studies and a murine model. Neuropsychopharmacology. 2018;43:342–53.CrossRefGoogle Scholar
  46. 46.
    Iurato S, Carrillo-Roa T, Arloth J, Czamara D, Diener-Holzl L, Lange J, et al. DNA methylation signatures in panic disorder. Transl Psychiatry. 2017;7:1287.CrossRefGoogle Scholar
  47. 47.
    Gadermann AM, Alonso J, Vilagut G, Zaslavsky AM, Kessler RC. Comorbidity and disease burden in the National Comorbidity Survey Replication (NCS-R). Depress Anxiety. 2012;29:797–806.CrossRefGoogle Scholar
  48. 48.
    • Meier SM, Petersen L, Mattheisen M, Mors O, Mortensen PB, Laursen TM. Secondary depression in severe anxiety disorders: a population-based cohort study in Denmark. Lancet Psychiatry. 2015;2:515–23 This analysis highlights the need for cross-disorder analyses between anxiety and affective disorders.CrossRefGoogle Scholar
  49. 49.
    Meier SM, Uher R, Mors O, Dalsgaard S, Munk-Olsen T, Laursen TM, et al. Specific anxiety disorders and subsequent risk for bipolar disorder: a nationwide study. World Psychiatry. 2016;15:187–8.CrossRefGoogle Scholar
  50. 50.
    Meier SM, Petersen L, Pedersen MG, Arendt MC, Nielsen PR, Mattheisen M, et al. Obsessive-compulsive disorder as a risk factor for schizophrenia: a nationwide study. JAMA Psychiatry. 2014;71:1215–21.CrossRefGoogle Scholar
  51. 51.
    Smoller JW. The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology. 2016;41:297–319.CrossRefGoogle Scholar
  52. 52.
    Cross-Disorder Group of the Psychiatric Genomics C. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–9.CrossRefGoogle Scholar
  53. 53.
    Turley P, Walters RK, Maghzian O, Okbay A, Lee JJ, Fontana MA, et al. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat Genet. 2018;50:229–37.CrossRefGoogle Scholar
  54. 54.
    Maier RM, Zhu Z, Lee SH, Trzaskowski M, Ruderfer DM, Stahl EA, et al. Improving genetic prediction by leveraging genetic correlations among human diseases and traits. Nat Commun. 2018;9:989.CrossRefGoogle Scholar
  55. 55.
    Zhu Z, Zheng Z, Zhang F, Wu Y, Trzaskowski M, Maier R, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat Commun. 2018;9:224.CrossRefGoogle Scholar
  56. 56.
    Krapohl E, Hannigan LJ, Pingault JB, Patel H, Kadeva N, Curtis C, et al. Widespread covariation of early environmental exposures and trait-associated polygenic variation. Proc Natl Acad Sci U S A. 2017;114:11727–32.CrossRefGoogle Scholar
  57. 57.
    Uher R. Gene-environment interactions in severe mental illness. Front Psychiatry. 2014;5:48.CrossRefGoogle Scholar
  58. 58.
    Klauke B, Deckert J, Reif A, Pauli P, Domschke K. Life events in panic disorder—an update on “candidate stressors”. Depress Anxiety. 2010;27:716–30.CrossRefGoogle Scholar
  59. 59.
    Dudbridge F, Fletcher O. Gene-environment dependence creates spurious gene-environment interaction. Am J Hum Genet. 2014;95:301–7.CrossRefGoogle Scholar
  60. 60.
    Ruderfer DM, Charney AW, Readhead B, Kidd BA, Kahler AK, Kenny PJ, et al. Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. Lancet Psychiatry. 2016;3:350–7.CrossRefGoogle Scholar
  61. 61.
    •• Breen G, Li Q, Roth BL, O'Donnell P, Didriksen M, Dolmetsch R, et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci. 2016;19:1392–6 This study demonstrates that genetic findings can inform the development of novel therapeutics. Google Scholar
  62. 62.
    Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov. 2013;12:581–94.CrossRefGoogle Scholar
  63. 63.
    Torkamani A, Wineinger NE, Topol EJ. The personal and clinical utility of polygenic risk scores. Nat Rev Genet. 2018.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PsychiatryDalhousie UniversityHalifaxCanada
  2. 2.Child and Adolescent Mental Health Centre–Mental Health Services Capital RegionCopenhagen RegionDenmark
  3. 3.Psychosis Research UnitAarhus University HospitalRisskovDenmark
  4. 4.Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental HealthUniversity of WürzburgWürzburgGermany

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