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Behavior Genetics

, Volume 34, Issue 3, pp 243–250 | Cite as

A Candidate Gene Study of CYP19 (Aromatase) and Male Sexual Orientation

  • Michael G. DuPree
  • Brian S. Mustanski
  • Sven Bocklandt
  • Caroline Nievergelt
  • Dean H. Hamer
Article

Abstract

Aromatase cytochrome P450 (CYP19), which is necessary for the conversion of androgens to estrogens, plays an important role in the sexual differentiation of the brain. To investigate whether differences in the gene encoding the aromatase enzyme influence sexual orientation in men, we conducted linkage, association, and expression analyses in a large sample of homosexual brothers using microsatellite markers in and around CYP19. No linkage was detected, and a gene-specific relative risk of 1.5-fold could be excluded at a lod score of −2. Results of the TDT demonstrated no preferential transmission of any of the CYP19 alleles in this sample. Expression of aromatase mRNA by microarray analysis was not significantly different between heterosexual and homosexual men. These results suggest that variation in the gene for this subunit of the aromatase enzyme complex is not likely to be a major factor in the development of individual differences in male sexual orientation.

Homosexuality sexual orientation aromatase CYP19 linkage expression 

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References

  1. Adkins-Regan, E., Mansukhani, V., Thompson, R., and Yang, S. (1997). Organizational actions of sex hormones on sexual partner preference. Brain Res. Bull. 44:497-502.Google Scholar
  2. Allen, L. S., and Gorski, R. A. (1992). Sexual orientation and the size of the anterior commissure in the human brain. Proc. Natl. Acad. Sci. USA 89:7199-7202.Google Scholar
  3. Arai, Y. (1972). Effect of 5-dihydrotestosterone on differentiation of masculine pattern of the brain in the rat. Endocrinol. Jpn. 19:389-393.Google Scholar
  4. Bailey, J. M., and Pillard, R. C. (1995). Genetics of human sexual orientation. Ann. Rev. of Sex Res. 6:126-150.Google Scholar
  5. Bailey, J. M., Pillard, R. C., Dawood, K., Miller, M. B., Farrer, L. A., Trivedi, S., and Murphy, R. L. (1999). A family history study of male sexual orientation using three independent samples. Behav. Genet. 29:79-86.Google Scholar
  6. Bailey, J. M., and Zucker, K. J. (1995). Childhood sex-typed behavior and sexual orientation: A conceptual analysis and quantitative review. Dev. Psychol. 31:43-55.Google Scholar
  7. Bakker, J., Honda, S., Harada, N., and Balthazart, J. (2002). Sexual partner preference requires a functional aromatase (Cyp19) gene in male mice. Horm. Behav. 42:158-171.Google Scholar
  8. Balthazart, J., Foidart, A., Surlemont, C., Harada, N., and Naftolin, F. (1992). Neuroanatomical specificity in the autoregulation of aromatase-immunoreactive neurons by androgens and estrogens: An immunocytochemical study. Brain Res. 6:280-290.Google Scholar
  9. Beyer, C., Morali, G., Naftolin, F., Larsson, K., and Perez, P. (1976). Effect of some antiestrogens and aromatase inhibitors on androgen induced sexual behavior in castrated male rats. Horm. Behav. 7:353-363.Google Scholar
  10. Byne, W., Tobet, S., Mattiace, L., Lasco, M. S., Kemether, E., Edgar, M. A., Morgello, S., Buchsbaum, M. S., and Jones, L. B. (2001). The interstitial nuclei of the human anterior hypothalamus: An investigation of variation within sex, sexual orientation and HIV status. Horm. Behav. 40:86-92.Google Scholar
  11. Carani, C., Qin, K., Simoni, M., Faustini-Fustini, M., Serpente, S., Boyd, J., Korach, K. S., and Simpson, E. R. (1997). Effect of testosterone and estradiol in a man with aromatase deficiency. N. Engl. J. Med. 337:91-95.Google Scholar
  12. Carreau, S. (2000). Estrogens and male reproduction. Folia Histochem. Cytobiol. 38:47-52.Google Scholar
  13. Chen, S. A., Besman, M. J., Sparkes, R. S., Zollman, S., Klisak, I., Mohandas, T., Hal, I. P. F., and Shively, J. E. (1988). Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA 7:27-38.Google Scholar
  14. Conley, A., and Hinshelwood, M. (2001). Mammalian aromatases. Reproduction 121:685-695.Google Scholar
  15. Couse, J. F., and Korach, K. S. (1999). Estrogen receptor null mice: What have we learned and where will they lead us? Endocr. Rev. 20:358-417.Google Scholar
  16. Diamond, M. (1993). Homosexuality and bisexuality in different populations. Arch. Sex. Behav. 22:291-310.Google Scholar
  17. Dorner, G. (1976). Hormones and Brain Sexual Differentiation. Amsterdam: Elsevier.Google Scholar
  18. Eisen, M. B., and Brown, P. O. (1999). DNA arrays for analysis of gene expression. Methods Enzymol. 303:179-205.Google Scholar
  19. Ellis, L., and Ames, M. A. (1987). Neurohormonal functioning and sexual orientation: A theory of homosexuality/heterosexuality. Psychol. Bull. 101:233-258.Google Scholar
  20. Faustini-Fustini, M., Rochira, V., and Carani, C. (1999). Oestrogen deficiency in men: Where are we today? Eur. J. Endocrinol. 140:111-129.Google Scholar
  21. Fisher, C. R., Graves, K. H., Parlow, A. F., and Simpson, E. R. (1998). Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc. Natl. Acad. Sci. USA 95:6965-6970.Google Scholar
  22. Gorski, R. A. (1991). Sexual differentiation of the endocrine brain and its control. In M. Motta (ed.), Brain Endocrinology (Vol. 2, pp. 71-104). New York: Raven.Google Scholar
  23. Goy, R. W., and McEwen, B. S. (1980). Sexual Differentiation of the Brain. Cambridge, MA: MIT Press.Google Scholar
  24. Haldane, J. B. S. (1919). The combination of linkage values and the calculation of distances between the loci of linked factors. J. Genet. 8:299-309.Google Scholar
  25. Hamer, D. (1999). Genetics and male sexual orientation. Science 285:803.Google Scholar
  26. Hamer, D., and Copeland, P. (1994). The Science of Desire: The Search for the Gay Gene. New York: Simon & Schuster.Google Scholar
  27. Hamer, D. H., Hu, S., Magnuson, V. L., Hu, N., and Pattatucci, A. M. (1993). A linkage between DNA markers on the X chromosome and male sexual orientation. Science 261:321-327.Google Scholar
  28. Hayes, F. J., Seminara, S. B., Decruz, S., Boepple, P. A., and Crowley Jr., W. F. (2000). Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback. J. Clin. Endocrinol. Metab. 85:3027-3035.Google Scholar
  29. Herrmann, B. L., Saller, B., Janssen, O. E., Gocke, P., Bockisch, A., Sperling, H., Mann, K., and Broecker, M. (2002). Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. J. Clin. Endocrinol. Metab. 87:5476-5484.Google Scholar
  30. Hinds, D., and Risch, N. (1996). The ASPEX package: Affected sib-pair mapping. Available at ftp://lahmed.stanford.edu/pub/ aspex.Google Scholar
  31. Honda, S., Harada, N., Ito, S., Takagi, Y., and Maeda, S. (1998). Disruption of sexual behavior in male aromatase-deficient mice lacking exons 1 and 2 of the cyp19 gene. Biochem. Biophys. Res. Commun. 252:445-449.Google Scholar
  32. Hu, S., Pattatucci, A. M., Patterson, C., Li, L., Fulker, D. W., Cherny, S. S., Kruglyak, L., and Hamer, D. H. (1995). Linkage between sexual orientation and chromosome Xq28 in males but not in females. Nat. Genet. 11:248-256.Google Scholar
  33. Hutchison, J. B. (1997). Gender-specific steroid metabolism in neural differentiation. Cell. Mol. Neurobiol. 17:603-626.Google Scholar
  34. Kendler, K. S., Thornton, L. M., Gilman, S. E., and Kessler, R. C. (2000). Sexual orientation in a U.S. national sample of twin and nontwin sibling pairs. Am. J. Psychiatry 157:1843-1846.Google Scholar
  35. Kinsey, A. C., Pomeroy, W. B., and Martin, C. E. (1948). Sexual Behavior in the Human Male. Bloomington, IN: Indiana University Press.Google Scholar
  36. Kirk, K. M., Bailey, J. M., Dunne, M. P., and Martin, N. G. (2000). Measurement models for sexual orientation in a community twin sample. Behav. Genet. 30:345-356.Google Scholar
  37. Kruglyak, L., and Lander, E. (1995). Complete multipoint sib pair analysis of qualitative and quantitative traits. Am J. Hum Genet. 57:439-454.Google Scholar
  38. Lalumière, M. L., Blanchard, R., and Zucker, K. J. (2000). Sexual orientation and handedness in men and women: A meta-analysis. Psychol. Bull. 126:575-592.Google Scholar
  39. Lander, E., and Kruglyak, L. (1995). Genetic dissection of complex traits: Guidelines for interpreting and reporting linkage results. Nat. Genet. 11:241-247.Google Scholar
  40. Lasco, M. S., Jordan, T. J., Edgar, M. A., Petito, C. K., and Byne, W. (2002). A lack of dimorphism of sex or sexual orientation in the human anterior commissure. Brain Res. 936:95-98.Google Scholar
  41. Laumann, E. O., Gagnon, J. H., Michael, R. T., and Michaels, S. (1994). The Social Organization of Sexuality: Sexual Practices in the United States. Chicago: University of Chicago Press.Google Scholar
  42. Lephart, E. D. (1996). A review of brain aromatase cytochrome P450. Brain. Res. Rev. 22:1-26.Google Scholar
  43. LeVay, S. (1991). A difference in hypothalamic structure between heterosexual and homosexual men. Science 253:1034-1037.Google Scholar
  44. Luttge, W. G., and Whalen, R. E. (1970). Regional localization of estrogenic metabolites in the brain of male and female rats. Steroids 15:605-612.Google Scholar
  45. Macke, J. P., Hu, N., Hu, S., Bailey, M., King, V. L., Brown, T., Hamer, D., and Nathans, J. (1993b). Sequence variation in the androgen receptor gene is not a common determinant of male sexual orientation. Am. J. Hum. Genet. 53:844-852.Google Scholar
  46. MacLusky, N. J., and Naftolin, F. (1981). Sexual differentiation of the central nervous system. Science 211:1294-1302.Google Scholar
  47. Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., and Qin, K. (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J. Clin. Endocrinol. Metab. 80:3689-3698.Google Scholar
  48. Mustanski, B. S., Chivers, M. L., and Bailey, J. M. (2002). A critical review of recent biological research on human sexual orientation. Ann. Rev. Sex Res. 13:89-140.Google Scholar
  49. Ogawa, S., Chester, A. E., Hewitt, S. C., Walker, V. R., Gustafsson, J. A., Smithies, O., Korach, K. S., and Pfaff, D. W. (2000). Abolition of male sexual behaviors in mice lacking estrogen receptors alpha and beta (alpha beta ERKO). Proc. Natl. Acad. Sci. USA 97:14737-14741.Google Scholar
  50. Ogawa, S., Lubahn, D. B., Korach, K. S., and Pfaff, D. W. (1997). Behavioral effects of estrogen receptor gene disruption in male mice. Proc. Natl. Acad. Sci. USA 94:1476-1481.Google Scholar
  51. Pilgrim, C., and Reisert, I. (1992). Differences between male and female brains: Developmental mechanisms and implications. Horm. Metab. Res. 24:353-359.Google Scholar
  52. Pinckard, K. L., Stellflug, J., Resko, J. A., Roselli, C. E., and Stormshak, F. (2000). Review: Brain aromatization and other factors affecting male reproductive behavior with emphasis on the sexual orientation of rams. Domest. Anim. Endocrinol. 18:83-96.Google Scholar
  53. Polymeropoulos, M. H., Xiao, H., Rath, D. S., and Merril, C. R. (1991). Tetranucleotide repeat polymorphism at the human aromatase cytochrome P-450 gene (CYP19). Nucleic Acids Res. 19:195.Google Scholar
  54. Rice, G., Anderson, C., Risch, N., and Ebers, G. (1999). Male homosexuality: Absence of linkage to microsatellite markers at X, 28. Science. Apr. 23; 284(5414):665-667.Google Scholar
  55. Risch, N. (1990). Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am. J. Hum. Genet. 46:229-241.Google Scholar
  56. Sabol, S. Z., Nelson, M. L., Fisher, C., Gunzerath, L., Brody, C. L., Hu, S., Sirota, L. A., Marcus, S. E., Greenberg, B. D., Lucas, F. R. T., Benjamin, J., Murphy, D. L., and Hamer, D. H. (1999). A genetic association for cigarette smoking behavior. Health Psychol. 18:7-13.Google Scholar
  57. Shephard, E. A., Phillips, I. R., Santisteban, I., West, L. F., Palmer, C. N., Ashworth, A., and Povey, S. (1989). Isolation of a human cytochrome P-450 reductase cDNA clone and localization of the corresponding gene to chromosome 7q11.2. Ann. Hum. Genet. 53:291-301.Google Scholar
  58. Stoffel-Wagner, B., Watzka, M., Schramm, J., Bidlingmaier, F., and Klingmuller, D. (1999). Expression of CYP19 (aromatase) mRNA in different areas of the human brain. J. Steroid Biochem. Mol. Biol. 70:237-241.Google Scholar
  59. Swaab, D. F., and Hofman, M. A. (1990). An enlarged suprachiasmatic nucleus in homosexual men. Brain Res. 537:141-148.Google Scholar
  60. Waterman, M. R. (1995). Cytochrome P450. In R. A. Meyers (ed.), Molecular Biology and Biotechnology: A Comprehensive Desk Reference (pp. 197-200). New York: VCH Publisher.Google Scholar
  61. Weber, J. L., and May, P. E. (1989). Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. Hum. Genet. 44:388-396.Google Scholar
  62. Wellings, K., Field, J., Johnson, A., and Wadsworth, J. (1994). Sexual Behaviour in Britain. New York: Penguin Books.Google Scholar
  63. Williams, T. J., Pepitone, M. E., Christensen, S. E., Cooke, B. M., Huberman, A. D., Breedlove, N. J., Breedlove, T. J., Jordan, C. L., and Breedlove, S. M. (2000). Finger-length ratios and sexual orientation. Nature 404:455-456.Google Scholar
  64. Wilson, J. D., Griffin, J. E., George, F. W., and Leshin, M. (1981). The role of gonadal steroids in sexual differentiation. Recent Prog. Horm. Res. 37:1-39.Google Scholar
  65. Zhou, J. N., Hofman, M. A., and Swaab, D. F. (1995). No changes in the number of vasoactive intestinal polypeptide (VIP)-expressing neurons in the suprachiasmatic nucleus of homosexual men: Comparison with vasopressin-expressing neurons. Brain Res. 672:285-288.Google Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Michael G. DuPree
    • 1
    • 2
    • 3
  • Brian S. Mustanski
    • 1
    • 4
  • Sven Bocklandt
    • 1
  • Caroline Nievergelt
    • 5
  • Dean H. Hamer
    • 1
  1. 1.Laboratory of BiochemistryNational Cancer Institute, National Institutes of HealthBethesda
  2. 2.Department of AnthropologyPennsylvania State UniversityUniversity Park
  3. 3.Center for Neurobehavioral GeneticsUniversity of CaliforniaLos Angeles
  4. 4.Department of PsychologyIndiana UniversityBloomington
  5. 5.Department of PsychiatryUniversity of CaliforniaSan Diego

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