Behavior Genetics

, 36:147

New Approaches to the Genetic Analysis of Neuroticism and Anxiety

Article

Abstract

The completion of the human genome project and the complementary genome projects for other species has broadened the scope for novel bioinformatic approaches to quantitative trait locus (QTL) identification. A key issue for quantitative trait nucleotide (QTN) identification is progressing from a large QTL peak, spanning perhaps 50 cM and many hundreds of genes, to a gene or nucleotide variant which is responsible for that QTL effect. The complementary use of mouse models to dissect large syntenic loci in humans is a powerful method for reducing QTL intervals to the order of 1 Mb. This paper presents an overview of the approaches used in our laboratory to ultra-fine map QTLs for anxiety-related traits, and to identify quantitative trait genes (QTG). As new genetic techniques and statistical approaches arise, we are getting closer to identifying those long sought after QTNs.

Keywords

Anxiety behaviour human mapping mouse neuroticism outbred personality quantitative trait quantitative trait gene 

References

  1. Abiola O., Angel J. M., Avner P., Bachmanov A. A., Belknap J. K., Bennett B., Blankenhorn E. P., Blizard D. A. et al. (2003). The nature and identification of quantitative trait loci: a community’s view. Nat. Rev. Genet. 4(11):911–916PubMedCrossRefGoogle Scholar
  2. Abkevich V., Camp N.J., Hensel C.H., Neff C.D., Russell D.L., Hughes D.C., Plenk A.M., Lowry M.R., et al. (2003). Predisposition locus for major depression at chromosome 12q22–12q23.2. Am. J. Hum. Genet. 73(6):1271–1281CrossRefPubMedGoogle Scholar
  3. Caldarone B., Saavedra C., Tartaglia K., Wehner J. M., Dudek B. C., Flaherty L. (1997). Quantitative trait loci analysis affecting contextual conditioning in mice. Nat. Genet. 17(3): 335–337PubMedCrossRefGoogle Scholar
  4. Camp N. J., Lowry M. R., Richards R. L., Plenk A. M., Carter C., Hensel C. H., Abkevich V., Skolnick M. H., Shattuck D., Rowe K. G., Hughes D. C., Cannon-Albright L. A. (2005). Genome-wide linkage analyses of extended Utah pedigrees identifies loci that influence recurrent, early-onset major depression and anxiety disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 135(1): 85–93PubMedGoogle Scholar
  5. Cloninger C. R. (1994). Temperament and personality. Curr. Opin. Neurobiol. 4: 266–273CrossRefPubMedGoogle Scholar
  6. Cloninger C. R., Van Eerdewegh P., Goate A., Edenberg H. J., Blangero J., Hesselbrock V., Reich T., Nurnberger J. Jr. et al. (1998). Anxiety proneness linked to epistatic loci in genome scan of human personality traits. Am. J. Med. Genet. 81(4): 313–317CrossRefPubMedGoogle Scholar
  7. Curtis D. (2004). Re-analysis of collaborative study on the genetics of alcoholism pedigrees suggests the presence of loci influencing novelty-seeking near D12S391 and D17S1299. Psychiatr. Genet. 14(3): 151–155CrossRefPubMedGoogle Scholar
  8. Digman J. M. (1990). Personality structure: emergence of the 5-factor model. Ann. Rev. Psychol. 41:417–440Google Scholar
  9. Dina C., Nemanov L., Gritsenko I., Rosolio N., Osher Y., Heresco-Levy U., Sariashvilli E., Bachner-Melman R., Zohar A. H., Benjamin J., Belmaker R. H., Ebstein R. P. (2005). Fine mapping of a region on chromosome 8p gives evidence for a QTL contributing to individual differences in an anxiety-related personality trait: TPQ harm avoidance. Am. J. Med. Genet. B Neuropsychiatr. Genet. 132(1):104–108PubMedGoogle Scholar
  10. Dreary, I. J., and Matthews, G. (1993). Personality traits are alive and well. The Psychologist 299–311Google Scholar
  11. Duggan C., Sham P., Lee A., Minne C., Murray R. (1995). Neuroticism: a vulnerability marker for depression evidence from a family study. J. Affect Disord. 35(3): 139–143CrossRefPubMedGoogle Scholar
  12. Duggan C. F., Lee A. S., Murray R. M. (1990). Does personality predict long-term outcome in depression?. Br. J. Psychiatry 157: 19–24PubMedCrossRefGoogle Scholar
  13. Durrant C., Zondervan K. T., Cardon L. R., Hunt S., Deloukas P., Morris A. P. (2004). Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes. Am. J. Hum. Genet. 75(1):35–43CrossRefPubMedGoogle Scholar
  14. Eysenck H., Eysenck S. (1975). Manual of the Eysenck Personality Questionnaire. San Diego, CA, Educational and Industrial Testing ServiceGoogle Scholar
  15. Farmer A., Breen G., Brewster S., Craddock N., Gill M., Korszun A., Maier W., Middleton L. et al. (2004). The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study. BMC Psychiatry 4(1):42CrossRefPubMedGoogle Scholar
  16. Fernandez-Teruel A., Escorihuela R. M., Gray J. A., Aguilar R., Gil L., Gimenez-Llort L., Tobena A., Bhomra A., Nicod A., Mott R., Driscoll P., Dawson G. R., Flint J. (2002). A quantitative trait locus influencing anxiety in the laboratory rat. Genome Res. 12(4): 618–626PubMedCrossRefGoogle Scholar
  17. Flint J. (2004). The genetic basis of neuroticism. Neurosci. Behav. Rev. 28:307–316Google Scholar
  18. Flint J., Corley R., DeFries J.C., Fulker D.W., Gray J.A., Miller S., Collins A.C. (1995). A simple genetic basis for a complex psychological trait in laboratory mice. Science 269(5229):1432–1435PubMedCrossRefGoogle Scholar
  19. Flint J., Valdar W., Shifman S., Mott R. (2005). Strategies for mapping and cloning quantitative trait genes in rodents. Nat. Rev. Genet. 6(4):271–286CrossRefPubMedGoogle Scholar
  20. Fullerton J., Cubin M., Tiwari H., Wang C., Bomhra A., Davidson S., Miller S., Fairburn C., Goodwin G., Neale M. C., Fiddy S., Mott R., Allison D. B., Flint J. (2003). Linkage analysis of extremely discordant and concordant sibling pairs identifies quantitative-trait loci that influence variation in the human personality trait neuroticism. Am. J. Hum. Genet. 72(4): 879–890CrossRefPubMedGoogle Scholar
  21. Gelernter J., Bonvicini K., Page G., Woods S. W., Goddard A. W., Kruger S., Pauls D. L., Goodson S. (2001). Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am. J. Med. Genet. 105(6): 548–557CrossRefPubMedGoogle Scholar
  22. Gelernter J., Page G. P., Bonvicini K., Woods S. W., Pauls D. L., Kruger S. (2003). A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol. Psychiatry 8(1): 71–82CrossRefPubMedGoogle Scholar
  23. Gelernter J., Page G. P., Stein M. B., Woods S. W. (2004). Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus. Am. J. Psychiatry 161(1):59–66CrossRefPubMedGoogle Scholar
  24. Gershenfeld H. K., Neumann P. E., Mathis C., Crawley J. N., Li X., Paul S. M. (1997). Mapping quantitative trait loci for open-field behavior in mice. Behav. Genet. 27(3): 201–210CrossRefPubMedGoogle Scholar
  25. Gray J. A. (1982). The Neuropsychology of Anxiety: An Enquiry into the Function of the Septo-hippocampal System. Oxford, Oxford University PressGoogle Scholar
  26. Gray J. A. (1987). The Psychology of Fear and Stress. Cambridge, Cambridge University PressGoogle Scholar
  27. Gray J. A., McNaughton N. (2000). The Neuropsychology of Anxiety. Oxford, Oxford University PressGoogle Scholar
  28. Hettema J. M., Prescott C. A., Kendler K. S. (2004). Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism. Am. J. Psychiatry 161(9):1581–1587CrossRefPubMedGoogle Scholar
  29. Higgs D. R., Wood W. G., Jarman A. P., Sharpe J., Lida J., Pretorius I. M., Ayyub H. (1990). A major positive regulatory region located far upstream of the human alpha-globin gene locus. Genes Dev. 4(9):1588–1601PubMedCrossRefGoogle Scholar
  30. Hirschfeld R. M., Klerman G. L., Lavori P., Keller M. B., Griffith P., Coryell W. (1989). Premorbid personality assessments of first onset of major depression. Arch. Gen. Psychiatry 46(4):345–350PubMedGoogle Scholar
  31. Holmans P., Zubenko G. S., Crowe R. R., DePaulo J. R. Jr., Scheftner W. A., Weissman M. M., Zubenko W. N., Boutelle S. et al. (2004). Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q. Am. J. Hum. Genet. 74(6): 1154–1167CrossRefPubMedGoogle Scholar
  32. Ke X., Hunt S., Tapper W., Lawrence R., Stavrides G., Ghori J., Whittaker P., Collins A., Morris A. P., Bentley D., Cardon L. R., Deloukas P. (2004). The impact of SNP density on fine-scale patterns of linkage disequilibrium. Hum. Mol. Genet. 13(6):577–588CrossRefPubMedGoogle Scholar
  33. Kendler K. S., Kuhn J., Prescott C. A. (2004). The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am. J. Psychiatry 161(4):631–636CrossRefPubMedGoogle Scholar
  34. Kessler R. C., Bergland P., Demler O., Jin R., Koretz D., Merikangas K., Rush A. J., Walters E. E., Wang P. S. (2003). The epidimiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095–3105CrossRefPubMedGoogle Scholar
  35. Khan A. A., Jacobson K. C., Gardner C. O., Prescott C. A., Kendler K. S. (2005). Personality and comorbidity of common psychiatric disorders. Br. J. Psychiatry 186:190–196CrossRefPubMedGoogle Scholar
  36. Kong X., Murphy K., Raj T., He C., White P. S., Matise T. C. (2004). A combined linkage-physical map of the human genome. Am. J. Hum. Genet. 75(6): 1143–1148CrossRefPubMedGoogle Scholar
  37. Lake R. I., Eaves L. J., Maes H. H., Heath A. C., Martin N. G. (2000). Further evidence against the environmental transmission of individual differences in neuroticism from a collaborative study of 45,850 twins and relatives on two continents. Behav. Genet. 30(3):223–233CrossRefPubMedGoogle Scholar
  38. Lettice L. A., Horikoshi T., Heaney S. J., van Baren M. J., van der Linde H. C., Breedveld G. J., Joosse M., Akarsu N. et al. (2002). Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl. Acad. Sci. USA 99(11):7548–7553CrossRefPubMedGoogle Scholar
  39. Levinson D.F. (2005). Meta-analysis in psychiatric genetics. Curr. Psychiatry Rep. 7(2):143–151PubMedCrossRefGoogle Scholar
  40. Loehlin J. C., Nichols R. C. (1976). Heredity, Environment and Personality. Austin, University of Texas PressGoogle Scholar
  41. Martin N., Goodwin G., Fairburn C., Wilson R., Allison D., Cardon L. R., Flint J. (2000). A population-based study of personality in 34,000 sib-pairs. Twin Res. 3(4): 310–315CrossRefPubMedGoogle Scholar
  42. McClearn G., Wilson J., Meredith W. (1970). Contributions to Behaviour-Genetic Analysis: The Mouse as a Prototype. New York, Appleton Cenury CroftsGoogle Scholar
  43. Mott R., Talbot C. J., Turri M. G., Collins A. C., Flint J. (2000). A method for fine mapping quantitative trait loci in outbred animal stocks. Proc. Natl. Acad. Sci. USA 97(23):12649–12654CrossRefPubMedGoogle Scholar
  44. Nash M. W., Huezo-Diaz P., Williamson R. J., Sterne A., Purcell S., Hoda F., Cherny S. S., Abecasis G. R. et al. (2004). Genome-wide linkage analysis of a composite index of neuroticism and mood-related scales in extreme selected sibships. Hum. Mol. Genet. 13(19): 2173–282CrossRefPubMedGoogle Scholar
  45. Neale B. M., Sullivan P. F., Kendler K. S. (2005). A genome scan of neuroticism in nicotine dependent smokers. Am. J. Med. Genet. B Neuropsychiatr. Genet. 132(1):65–69PubMedGoogle Scholar
  46. Nobrega M. A., Ovcharenko I., Afzal V., Rubin E. M. (2003). Scanning human gene deserts for long-range enhancers. Science 302(5644): 413CrossRefPubMedGoogle Scholar
  47. Nurnberger J. I. Jr., Foroud T., Flury L., Su J., Meyer E. T., Hu K., Crowe R., Edenberg H., Goate A., Bierut L., Reich T., Schuckit M., Reich W. (2001). Evidence for a locus on chromosome 1 that influences vulnerability to alcoholism and affective disorder. Am. J. Psychiatry 158(5):718–724CrossRefPubMedGoogle Scholar
  48. Oliveira-Dos-Santos A. J., Matsumoto G., Snow B. E., Bai D., Houston F. P., Whishaw I. Q., Mariathasan S., Sasaki T., Wakeham A., Ohashi P. S., Roder J.C., Barnes C. A., Siderovski D. P., Penninger J. M. (2000). Regulation of T cell activation, anxiety, and male aggression by RGS2. Proc. Natl. Acad. Sci. USA 97(22):12272–12277CrossRefPubMedGoogle Scholar
  49. Risch N., Merikangas K. (1996). The future of genetic studies of complex human diseases. Science 273(5281): 1516–1517PubMedCrossRefGoogle Scholar
  50. Risch N., Zhang H. (1995). Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268(5217):1584–1589PubMedCrossRefGoogle Scholar
  51. Roberts S. B., MacLean C. J., Neale M. C., Eaves L. J., Kendler K. S. (1999). Replication of linkage studies of complex traits: an examination of variation in location estimates. Am. J. Hum Genet. 65:876–884CrossRefPubMedGoogle Scholar
  52. Roy A. (1990). Personality variables in depressed patients and normal controls. Neuropsychobiology 23(3): 119–123PubMedCrossRefGoogle Scholar
  53. Smoller J. W., Acierno J. S. Jr., Rosenbaum J. F., Biederman J., Pollack M. H., Meminger S., Pava J. A., Chadwick L. H., White C., Bulzacchelli M., Slaugenhaupt S. A. (2001). Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am. J. Med. Genet. 105(2): 195–206CrossRefPubMedGoogle Scholar
  54. Talbot C. J., Nicod A., Cherny S. S., Fulker D. W., Collins A. C., Flint J. (1999). High-resolution mapping of quantitative trait loci in outbred mice. Nat. Genet. 21(3): 305–308CrossRefPubMedGoogle Scholar
  55. Visscher P. M., Hopper J. L. (2001). Power of regression and maximum likelihood methods to map QTL from sib-pair and DZ twin data. Ann. Hum. Genet. 65(Pt 6): 583–601CrossRefPubMedGoogle Scholar
  56. Yalcin, B., Flint, J., and Mott, R. (2005). Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics 171(2): 673–681CrossRefPubMedGoogle Scholar
  57. Yalcin B., Willis-Owen S. A., Fullerton J., Meesaq A., Deacon R. M., Rawlins J. N., Copley R. R., Morris A. P., Flint J., Mott R. (2004). Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nat. Genet. 36(11):1197–1202CrossRefPubMedGoogle Scholar
  58. Zeiss A. M., Lewinsohn P. M. (1988). Enduring deficits after remissions of depression: a test of the scar hypothesis. Behav. Res. Ther. 26(2): 151–158CrossRefPubMedGoogle Scholar
  59. Zubenko G. S., Hughes H. B. 3rd., Maher B. S., Stiffler J. S., Zubenko W. N., Marazita M. L. (2002). Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early-onset, major depression. Am. J. Med. Genet. 114(8):980–987CrossRefPubMedGoogle Scholar
  60. Zubenko G. S., Maher B., Hughes H. B. 3rd, Zubenko W. N., Stiffler J. S., Kaplan B. B., Marazita M. L. (2003). Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent, early-onset, major depression. Am. J. Med. Genet. B Neuropsychiatr. Genet. 123(1):1–18CrossRefPubMedGoogle Scholar
  61. Zuckerman, M., Kuhlman, D. M., and Camac, C. (1988). What lies beyond E and N? Factor analysis of scales believed to measure basic dimensions of personality. J. Pers. Soc. Psychol. 54:96–107CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  1. 1.The Wellcome Trust Centre for Human GeneticsThe University of OxfordRoosevelt DriveUK
  2. 2.The Wellcome Trust Centre for Human GeneticsThe University of OxfordRoosevelt DriveUK

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