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A major role for common genetic variation in anxiety disorders

Abstract

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30–60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

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References

  1. 1.

    Kessler RC, Aguilar-Gaxiola S, Alonso J, Chatterji S, Lee S, Ormel J, et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol Psichiatr Soc. 2009;18:23–33.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Wittchen H-U, Jacobi F. Size and burden of mental disorders in Europe–a critical review and appraisal of 27 studies. Eur Neuropsychopharmacol. 2005;15:357–76.

    CAS  PubMed  Google Scholar 

  3. 3.

    GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–858.

    Google Scholar 

  4. 4.

    Polderman TJC, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, et al. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nat Genet. 2015;47:702–9.

    CAS  PubMed  Google Scholar 

  5. 5.

    Craske MG, Stein MB, Eley TC, Milad MR, Holmes A, Rapee RM, et al. Anxiety disorders. Nat Rev Dis Prim. 2017;3:17024.

    PubMed  Google Scholar 

  6. 6.

    Smoller JW. The genetics of stress-related disorders: PTSD, depression, and anxiety disorders. Neuropsychopharmacology. 2016;41:297–319.

    CAS  PubMed  Google Scholar 

  7. 7.

    Ripke S, O’Dushlaine C, Chambert K, Moran JL, Kähler AK, Akterin S, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45:1150–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Dunn EC, Sofer T, Gallo LC, Gogarten SM, Kerr KF, Chen C-Y, 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.

    Google Scholar 

  10. 10.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Craske MG, Rauch SL, Ursano R, Prenoveau J, Pine DS, Zinbarg RE. What is an anxiety disorder? Depress Anxiety. 2009;26:1066–85.

    PubMed  Google Scholar 

  12. 12.

    Waszczuk MA, Zavos HMS, Gregory AM, Eley TC. The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood. JAMA Psychiatry. 2014;71:905–16.

    PubMed  Google Scholar 

  13. 13.

    Roberson-Nay R, Eaves LJ, Hettema JM, Kendler KS, Silberg JL. Childhood separation anxiety disorder and adult onset panic attacks share a common genetic diathesis. Depress Anxiety. 2012;29:320–7.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    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.

    PubMed  Google Scholar 

  15. 15.

    Tambs K, Czajkowsky N, Røysamb 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.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Mackintosh M-A, Gatz M, Wetherell JL, Pedersen NL. A twin study of lifetime Generalized Anxiety Disorder (GAD) in older adults: genetic and environmental influences shared by neuroticism and GAD. Twin Res Hum Genet. 2006;9:30–7.

    PubMed  Google Scholar 

  17. 17.

    Hettema JM, Prescott CA, Kendler KS. Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am J Psychiatry. 2004;161:1581–7.

    PubMed  Google Scholar 

  18. 18.

    Hettema JM, Neale MC, Myers JM, Prescott CA, Kendler KS. A population-based twin study of the relationship between neuroticism and internalizing disorders. Am J Psychiatry. 2006;163:857–64.

    PubMed  Google Scholar 

  19. 19.

    Bienvenu OJ, Hettema JM, Neale MC, Prescott CA, Kendler KS. Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia, agoraphobia, and animal phobia. Am J Psychiatry. 2007;164:1714–21.

    PubMed  Google Scholar 

  20. 20.

    Plomin R, Haworth CMA, Davis OSP. Common disorders are quantitative traits. Nat Rev Genet. 2009;10:872–8.

    CAS  PubMed  Google Scholar 

  21. 21.

    McGrath LM, Weill S, Robinson EB, Macrae R, Smoller JW. Bringing a developmental perspective to anxiety genetics. Dev Psychopathol. 2012;24:1179–93.

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    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.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Pedersen CB, Bybjerg-Grauholm J, Pedersen MG, Grove J, Agerbo E, Bækvad-Hansen M, et al. The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders. Mol Psychiatry. 2018;23:6–14.

    CAS  PubMed  Google Scholar 

  24. 24.

    Davis KAS, Coleman JRI, Adams M, Allen N, Breen G, Cullen B, et al. Mental health in UK Biobank: development, implementation and results from an online questionnaire completed by 157 366 participants. BJPsych Open. 2018;4:83–90.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kessler RC, Andrews G, Mroczek D, Ustun B, Wittchen H-U. The World Health Organization Composite International Diagnostic Interview short-form (CIDI-SF). Int J Methods Psychiatr Res. 1998;7:171–85.

    Google Scholar 

  26. 26.

    McLean CP, Asnaani A, Litz BT, Hofmann SG. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J Psychiatr Res. 2011;45:1027–35.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092–7.

    PubMed  Google Scholar 

  28. 28.

    Meier S, Trontti K, Als TD, Laine M, Pedersen MG, Bybjerg-Grauholm J et al. Genome-wide Association Study of Anxiety and Stress-related Disorders in the iPSYCH Cohort. BioRxiv 2018. https://doi.org/10.1101/263855.

  29. 29.

    Bycroft C, Freeman C, Petkova D, Band G, Elliott LT, Sharp K et al. Genome-wide genetic data on ~500,000 UK Biobank participants. BioRxiv 2017. https://doi.org/10.1101/166298.

  30. 30.

    R Foundation for Statistical Computing RCT. R: A Language and Environment for Statistical Computing. Vienna; 2017.

  31. 31.

    Loh P-R, Tucker G, Bulik-Sullivan BK, Vilhjálmsson BJ, Finucane HK, Salem RM, et al. Efficient Bayesian mixed-model analysis increases association power in large cohorts. Nat Genet. 2015;47:284–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bulik-Sullivan BK, Loh P-R, Finucane HK, Ripke S, Yang J, Schizophrenia Working Group of the Psychiatric Genomics Consortium. et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet. 2015;47:291–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Rapid GWAS of thousands of phenotypes for 337,000 samples in the UK Biobank—Neale lab. http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobank. Accessed 18 Jul 2019.

  34. 34.

    Zheng J, Erzurumluoglu AM, Elsworth BL, Kemp JP, Howe L, Haycock PC, et al. LD Hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics. 2017;33:272–9.

    CAS  PubMed  Google Scholar 

  35. 35.

    Details and considerations of the UK Biobank GWAS — Neale lab. http://www.nealelab.is/blog/2017/9/11/details-and-considerations-of-the-uk-biobank-gwas. Accessed 18 Jul 2019.

  36. 36.

    de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Evangelou E, Ioannidis JPA. Meta-analysis methods for genome-wide association studies and beyond. Nat Rev Genet. 2013;14:379–89.

    CAS  PubMed  Google Scholar 

  40. 40.

    Machiela MJ, Chanock SJ. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics. 2015;31:3555–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    International Schizophrenia Consortium, Purcell SM, Wray NR, Stone JL, Visscher PM, O’Donovan MC, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–52.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Okbay A, Baselmans BML, De Neve J-E, 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Smith DJ, Escott-Price V, Davies G, Bailey MES, Colodro-Conde L, Ward J, et al. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci. Mol Psychiatry. 2016;21:749–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Spalek K, Coynel D, Freytag V, Hartmann F, Heck A, Milnik A, et al. A common NTRK2 variant is associated with emotional arousal and brain white-matter integrity in healthy young subjects. Transl Psychiatry. 2016;6:e758.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Correia CT, Coutinho AM, Sequeira AF, Sousa IG, Lourenço Venda L, Almeida JP, et al. Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes Brain Behav. 2010;9:841–8.

    CAS  PubMed  Google Scholar 

  46. 46.

    Kohli MA, Salyakina D, Pfennig A, Lucae S, Horstmann S, Menke A, et al. Association of genetic variants in the neurotrophic receptor-encoding gene NTRK2 and a lifetime history of suicide attempts in depressed patients. Arch Gen Psychiatry. 2010;67:348–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Murphy TM, Ryan M, Foster T, Kelly C, McClelland R, O’Grady J, et al. Risk and protective genetic variants in suicidal behaviour: association with SLC1A2, SLC1A3, 5-HTR1B &NTRK2 polymorphisms. Behav Brain Funct. 2011;7:22.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Torres CM, Siebert M, Bock H, Mota SM, Castan JU, Scornavacca F, et al. Tyrosine receptor kinase B gene variants (NTRK2 variants) are associated with depressive disorders in temporal lobe epilepsy. Epilepsy Behav. 2017;71:65–72.

    PubMed  Google Scholar 

  49. 49.

    Chen Z-Y, Jing D, Bath KG, Ieraci A, Khan T, Siao C-J, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry. 2009;14:1105–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Wang Z, Fan J, Gao K, Li Z, Yi Z, Wang L, et al. Neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene associated with treatment response to mood stabilizers in patients with bipolar I disorder. J Mol Neurosci. 2013;50:305–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Xu K, Anderson TR, Neyer KM, Lamparella N, Jenkins G, Zhou Z, et al. Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence. Pharmacogenomics J. 2007;7:368–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Howard DM, Adams MJ, Shirali M, Clarke T-K, Marioni RE, Davies G et al. Genome-wide association study of depression phenotypes in UK Biobank (n = 322,580) identifies the enrichment of variants in excitatory synaptic pathways. BioRxiv 2017. https://doi.org/10.1101/168732.

  54. 54.

    van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res. 2018;122:433–43.

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Gallagher MD, Posavi M, Huang P, Unger TL, Berlyand Y, Gruenewald AL, et al. A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression. Am J Hum Genet. 2017;101:643–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Jing H, Hao Y, Bi Q, Zhang J, Yang P. Intra-amygdala microinjection of TNF-α impairs the auditory fear conditioning of rats via glutamate toxicity. Neurosci Res. 2015;91:34–40.

    CAS  PubMed  Google Scholar 

  57. 57.

    Hettema JM, An SS, Neale MC, Bukszar J, van den OordEJCG, Kendler KS, et al. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry. 2006;11:752–62.

    CAS  PubMed  Google Scholar 

  58. 58.

    Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology. 2012;62:42–53.

    PubMed  Google Scholar 

  59. 59.

    Farach FJ, Pruitt LD, Jun JJ, Jerud AB, Zoellner LA, Roy-Byrne PP. Pharmacological treatment of anxiety disorders: current treatments and future directions. J Anxiety Disord. 2012;26:833–43.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sullivan PF, Agrawal A, Bulik CM, Andreassen OA, Børglum AD, Breen G, et al. Psychiatric genomics: an update and an agenda. Am J Psychiatry. 2018;175:15–27.

    PubMed  Google Scholar 

  61. 61.

    Hirschfeld RMA. The comorbidity of major depression and anxiety disorders: recognition and management in primary care. Prim Care Companion J Clin Psychiatry. 2001;3:244–54.

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Cohen BE, Edmondson D, Kronish IM. State of the art review: depression, stress, anxiety, and cardiovascular disease. Am J Hypertens. 2015;28:1295–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Carney RM, Freedland KE. Depression and coronary heart disease. Nat Rev Cardiol. 2017;14:145–55.

    PubMed  Google Scholar 

  64. 64.

    Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kraft P. Curses–winner’s and otherwise–in genetic epidemiology. Epidemiology. 2008;19:649–51. discussion 657.

    PubMed  Google Scholar 

  66. 66.

    Martin AR, Gignoux CR, Walters RK, Wojcik GL, Neale BM, Gravel S, et al. Human demographic history impacts genetic risk prediction across diverse populations. Am J Hum Genet. 2017;100:635–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, et al. Comparison of sociodemographic and health-related characteristics of UK biobank participants with those of the general population. Am J Epidemiol. 2017;186:1026–34.

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Huffman JE. Examining the current standards for genetic discovery and replication in the era of mega-biobanks. Nat Commun. 2018;9:5054.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research has been conducted using the UK Biobank Resource, under application 16577. This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. High performance computing facilities were funded with capital equipment grants from the GSTT Charity (TR130505) and Maudsley Charity (980). The research reported in this publication was supported by the National Institute of Mental Health of the US National Institutes of Health under Award Number U01 MH109514. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CK currently receives salary support from National Institute for Health Research (NIHR) and has previously received salary support from the Novo Nordisk UK Research Foundation, NIHR Biomedical Research Centre for Mental Health at South London and from the Maudsley National Health Service (NHS) Foundation Trust in the past. CR is supported by a grant from Fondation Peters to TE and GB. JH is supported by the National Institutes of Health grant R01 MH113665. The iPSYCH team acknowledges funding from the Lundbeck Foundation (grant no R102-A9118 and R155-2014-1724), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. K.L.P acknowledges funding from the Alexander von Humboldt Foundation and the Medical Research Council UK.

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KP, TE, MH, KKN and GB conceived the study. KP, JC, SMM, CR, HG and SWC performed statistical analyses. CH, CK, HG, JC and KP performed phenotype and data QC for the UKBB samples. MM supervised the pre and post GWAS analysis pipeline for the iPSYCH sample. OM, MN, MBH, JBG, PBM, TW, DMH and ADB provided and processed samples for the iPSYCH sample. KP, JC, TE, GB wrote the paper. MH, KD, JH, JD, AM, MM gave advice and feedback at several stages of data generation and paper writing. All authors reviewed the paper.

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Correspondence to Gerome Breen or Thalia C. Eley.

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Purves, K.L., Coleman, J.R.I., Meier, S.M. et al. A major role for common genetic variation in anxiety disorders. Mol Psychiatry 25, 3292–3303 (2020). https://doi.org/10.1038/s41380-019-0559-1

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