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.
Similar content being viewed by others
References
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):911–916
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):1271–1281
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): 335–337
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): 85–93
Cloninger C. R. (1994). Temperament and personality. Curr. Opin. Neurobiol. 4: 266–273
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): 313–317
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): 151–155
Digman J. M. (1990). Personality structure: emergence of the 5-factor model. Ann. Rev. Psychol. 41:417–440
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):104–108
Dreary, I. J., and Matthews, G. (1993). Personality traits are alive and well. The Psychologist 299–311
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): 139–143
Duggan C. F., Lee A. S., Murray R. M. (1990). Does personality predict long-term outcome in depression?. Br. J. Psychiatry 157: 19–24
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):35–43
Eysenck H., Eysenck S. (1975). Manual of the Eysenck Personality Questionnaire. San Diego, CA, Educational and Industrial Testing Service
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):42
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): 618–626
Flint J. (2004). The genetic basis of neuroticism. Neurosci. Behav. Rev. 28:307–316
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):1432–1435
Flint J., Valdar W., Shifman S., Mott R. (2005). Strategies for mapping and cloning quantitative trait genes in rodents. Nat. Rev. Genet. 6(4):271–286
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): 879–890
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): 548–557
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): 71–82
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):59–66
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): 201–210
Gray J. A. (1982). The Neuropsychology of Anxiety: An Enquiry into the Function of the Septo-hippocampal System. Oxford, Oxford University Press
Gray J. A. (1987). The Psychology of Fear and Stress. Cambridge, Cambridge University Press
Gray J. A., McNaughton N. (2000). The Neuropsychology of Anxiety. Oxford, Oxford University Press
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):1581–1587
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):1588–1601
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):345–350
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): 1154–1167
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):577–588
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):631–636
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 289:3095–3105
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 186:190–196
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): 1143–1148
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):223–233
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):7548–7553
Levinson D.F. (2005). Meta-analysis in psychiatric genetics. Curr. Psychiatry Rep. 7(2):143–151
Loehlin J. C., Nichols R. C. (1976). Heredity, Environment and Personality. Austin, University of Texas Press
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): 310–315
McClearn G., Wilson J., Meredith W. (1970). Contributions to Behaviour-Genetic Analysis: The Mouse as a Prototype. New York, Appleton Cenury Crofts
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):12649–12654
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): 2173–282
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):65–69
Nobrega M. A., Ovcharenko I., Afzal V., Rubin E. M. (2003). Scanning human gene deserts for long-range enhancers. Science 302(5644): 413
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):718–724
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):12272–12277
Risch N., Merikangas K. (1996). The future of genetic studies of complex human diseases. Science 273(5281): 1516–1517
Risch N., Zhang H. (1995). Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268(5217):1584–1589
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. 65:876–884
Roy A. (1990). Personality variables in depressed patients and normal controls. Neuropsychobiology 23(3): 119–123
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): 195–206
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): 305–308
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): 583–601
Yalcin, B., Flint, J., and Mott, R. (2005). Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics 171(2): 673–681
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):1197–1202
Zeiss A. M., Lewinsohn P. M. (1988). Enduring deficits after remissions of depression: a test of the scar hypothesis. Behav. Res. Ther. 26(2): 151–158
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):980–987
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):1–18
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. 54:96–107
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fullerton, J. New Approaches to the Genetic Analysis of Neuroticism and Anxiety. Behav Genet 36, 147–161 (2006). https://doi.org/10.1007/s10519-005-9000-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10519-005-9000-4