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  • Original Research Article
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A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan

Abstract

We conducted a 10 centimorgan (cM) linkage genome scan in a set of American extended pedigrees ascertained through probands with panic disorder. Several anxiety disorders segregate in these families. In this article, we describe results for simple phobia from 14 of these families (including 129 subjects of whom 57 are affected). A total of 422 markers were genotyped. Multipoint lod score analyses (fully parametric and simple parametric models) and nonparametric analyses were completed using ALLEGRO. We observed significant linkage of simple phobia to chromosome 14 markers. The highest lod score under a fully parametric model was 3.17, at marker D14S75, under a dominant model. Under a fully parametric recessive model, the maximum lod score, also at D14S75, was 2.86. Analysis under a simple parametric model resulted in lod scores of 3.70 (dominant model) or 3.30 (recessive model). The highest Zlr score observed was 3.93 (P=4.1×10−5). The Zlr score was >1 for an extensive region, >77 cM. In all, 12 of the 14 families studied provided positive or zero lod scores at marker D14S75 (dominant model). The homologous genomic region has been implicated by studies mapping quantitative trait loci for a mouse model of fear. The linkage peak may be regarded as highly promising, owing to the breadth of the peak, the convergence of results under different models of inheritance and different analysis methods, and the support from an animal model. This is the first genome scan linkage study for simple phobia, a common disorder that causes high morbidity in the US population.

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References

  1. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51: 8–19.

    Article  CAS  PubMed  Google Scholar 

  2. Magee W, Eaton WW, Wittchen H-U, McGonagle KA, Kessler RC . Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry 1996; 53: 159–168.

    Article  CAS  PubMed  Google Scholar 

  3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, revised. American Psychiatric Press: Washington, DC, 1987.

  4. Curtis GC, Magee WJ, Eaton WW, Wittchen HU, Kessler RC . Specific fears and phobias. Epidemiology and classification. Br J Psychiatry 1998; 173: 212–217.

    Article  CAS  PubMed  Google Scholar 

  5. Fyer AJ, Mannuzza S, Gallops MS, Martin LY, Aaronson C, Gorman JM et al. Familial transmission of simple phobias and fears. A preliminary report. Arch Gen Psychiatry 1990; 47: 252–256.

    Article  CAS  PubMed  Google Scholar 

  6. Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF . Specificity in familial aggregation of phobic disorders. Arch Gen Psychiatry 1995; 52: 564–573.

    Article  CAS  PubMed  Google Scholar 

  7. Kendler KS, Karkowski LM, Prescott CA . Fears and phobias: reliability and heritability. Psychol Med 1999; 29: 539–553.

    Article  CAS  PubMed  Google Scholar 

  8. Kendler KS, Myers J, Prescott CA, Neale MC . The genetic epidemiology of irrational fears and phobias in men. Arch Gen Psychiatry 2001; 58: 257–265.

    Article  CAS  PubMed  Google Scholar 

  9. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S et al. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet (Neuropsych Genet) 2001; 105: 548–557.

    Article  CAS  Google Scholar 

  10. Spitzer RL, Endicott J . Schedule for Affective Disorders and Schizophrenia: Lifetime version. New York Biometrics Research Division: New York State Psychiatric Institute, 1975.

    Google Scholar 

  11. Boehnke M . Estimating the power of a proposed linkage study: a practical computer simulation approach. Am J Hum Genet 1986; 39: 513–527.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. S.A.G.E. Statistical Analysis for Genetic Epidemiology, Release 3.1 (Statistical Analysis for Genetic Epidemiology, Release 2.2). Computer program package available from the Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, 1998.

  13. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McPeek MS, Sun L . Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 2000; 66: 1076–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kruglyak L, Daly MJ, Reeve–Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A . ALLEGRO, a new computer program for multipoint linkage analysis. Nat Genet 2000; 25: 12–13.

    Article  CAS  PubMed  Google Scholar 

  17. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Gen 1995; 11: 241–247.

    Article  CAS  Google Scholar 

  19. Genin E, Martinez M, Clerget-Darpoux F . Posterior probability of linkage and maximal lod score. Ann Hum Genet 1995; 59: 123–132.

    Article  CAS  PubMed  Google Scholar 

  20. Terwilliger JD, Shannon WD, Lathrop GM, Nolan JP, Goldin LR, Chase GA et al. True and false positive peaks in genomewide scans: applications of length-based sampling to linkage mapping. Am J Hum Genet 1997; 61: 430–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Visscher P, Haley C . True and false positive peaks in genomewide scans: the long and the short of it. Genet Epidemiol 2001; 20: 409–414.

    Article  CAS  PubMed  Google Scholar 

  22. Mahtani MM, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 1996; 14: 90–94.

    Article  CAS  PubMed  Google Scholar 

  23. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA et al. Results of a genome-wide genetic screen for panic disorder. Am J Med Genet (Neuropsych Genet) 1998; 81: 139–147.

    Article  CAS  Google Scholar 

  24. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes Jr R . Genomewide survey of panic disorder. Am J Med Genet (Neuropsych Genet) 2001; 105: 105–109.

    Article  CAS  Google Scholar 

  25. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC, 1994.

  26. Flint J, Corley R, DeFries JC, Fulker D, Gray JA, Miller S et al. A simple genetic basis for a complex psychological trait in laboratory mice. Science 1995; 269: 1432–1435.

    Article  CAS  PubMed  Google Scholar 

  27. Blake JA, Eppig JT, Richardson JE, Davisson MT . The Mouse Genome Database Group. The Mouse Genome Database (MGD), expanding genetic and genomic resources for the laboratory mouse. Nucleic Acids Res 2000; 28: 108–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mott R, Talbot CJ, Turri MG, Collins AC, Flint J . A method for fine mapping quantitative trait loci in outbred animal stocks. Proc Natl Acad Sci USA 2000; 97: 12 649–12 654.

    Article  Google Scholar 

  29. Smoller JW, Acierno Jr JS, Rosenbaum JF, Biederman J, Pollack MH, Meminger S et al. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet (Neuropsych Genet) 2001; 105: 195–206.

    Article  CAS  Google Scholar 

  30. Fendt M, Koch M, Schnitzler HU . Somatostatin in the pontine reticular formation modulates fear potentiation of acoustic startle response: an anatomical, electrophysiological, and behavioral study. J Neurosci 1996; 16: 3097–3103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Abelson JL, Nesse RM, Vinik A . Treatment of panic-like attacks with a long-acting analogue of somatostatin. J Clin Psychopharmacol 1990; 10: 128–132.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

G Kay and A Lacobelle provided excellent technical assistance. S Goodson, MD, assisted with diagnoses. This work was supported in part by funds from the U.S. Department of Veterans Affairs (the VA Medical Research Program, and the VA Connecticut–Massachusetts Mental Illness Research, Education and Clinical Center (MIRECC)), NIMH Grant K02-MH01387, and NIDA grants DA12849 and DA12690. Some homology data for this paper were retrieved from the Mouse Genome Database (MGD), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine (URL: http://www.informatics.jax.org/). (March 2001). Cell lines for many of the samples studied were initially established in the laboratory of Dr K Kidd. Some results of this paper were obtained by using the program package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (1 P41 RR03655). Finally, we wish to thank the families who participated in this research.

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Gelernter, J., Page, G., Bonvicini, K. et al. A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan. Mol Psychiatry 8, 71–82 (2003). https://doi.org/10.1038/sj.mp.4001224

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