Behavior Genetics

, Volume 35, Issue 6, pp 735–744 | Cite as

Opposite Effects of Androgen Receptor CAG Repeat Length on Increased Risk of Left-Handedness in Males and Females

  • Sarah E. Medland
  • David L. Duffy
  • Amanda B. Spurdle
  • Margaret J. Wright
  • Gina M. Geffen
  • Grant W. Montgomery
  • Nicholas G. Martin
Article

Abstract

Prenatal exposure to testosterone has been hypothesised to effect lateralization by influencing cell death in the foetal brain. Testosterone binds to the X chromosome linked androgen receptor, which contains a polymorphic polyglutamine CAG repeat, the length of which is positively correlated with testosterone levels in males, and negatively correlated in females. To determine whether the length of the androgen receptor mediates the effects of testosterone on laterality, we examined the association between the number of CAG repeats in the androgen receptor gene and handedness for writing. Association was tested by adding regression terms for the length of the androgen receptor alleles to a multi-factorial-threshold model of liability to left-handedness. In females we found the risk of left-handedness was greater in those with a greater number of repeats (p=0.04), this finding was replicated in a second independent sample of female twins (p=0.014). The length of the androgen receptor explained 6% of the total variance and 24% of the genetic variance in females. In males the risk of left-handedness was greater in those with fewer repeats (p=0.02), with variation in receptor length explaining 10% of the total variance and 24% of the genetic variance. Thus, consistent with Witelson’s theory of testosterone action, in all three samples the likelihood of left handedness increased in those individuals with variants of the androgen receptor associated with lower testosterone levels.

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References

  1. Anbazhagan, R., Gusterson, B. A. 1992Reversed cerebral asymmetry and breast cancerLancet3391056PubMedGoogle Scholar
  2. Annett, M. 1985Left, Right, Hand and Brain: The Right Shift TheoryLawrence Erlbaum AssociatesLondonGoogle Scholar
  3. Annett, M. 2002Handedness and Brain Asymmetry: The Right Shift TheoryPsychology PressHoveGoogle Scholar
  4. Bishop, D. 2001Individual differences in handedness and specific speech and language impairment: evidence against a genetic linkBehav. Genet.31339351CrossRefPubMedGoogle Scholar
  5. Chamberlain, N. L., Driver, E. D., Miesfeld, R. L. 1994The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation functionNucleic Acids Res.2231813186PubMedGoogle Scholar
  6. Choong, C., Kemppainen, J., Zhou, Z., Wilson, E. 1996Reduced androgen receptor gene expression with first exon CAG repeat expansionMol. Endocrinol.1015271535CrossRefPubMedGoogle Scholar
  7. Cornish, K., McManus, I. 1996Hand preference and hand skill in children with autismJ. Autism Dev. Disord.26597609CrossRefPubMedGoogle Scholar
  8. Elkadi, S., Nicholls, M., Clode, D. 1999Handedness in opposite and same-sex dizygotic twins: testing the testosterone hypothesisNeuroreport: An Int. J. Rapid Commun. Res. Neurosci.10333336Google Scholar
  9. Ewen, K. R., Bahlo, M., Treloar, S. A., Levinson, D. F., Mowry, B., Barlow, J. W., Foote, S. J. 2000Identification and analysis of error types in high-throughput genotypingAm. J. Human Genet.67727736Google Scholar
  10. Francks, C., Fisher, S., MacPhie, L., Richardson, A., Marlow, A., Stein, J., Monaco, A. 2002A genomewide linkage screen for relative hand skill in sibling pairsAm. J. Human Genet.70800805Google Scholar
  11. Gadea, M., Gomez, C., Gonzalez-Bono, E., Salvador, A., Espert, R. 2003Salivary testosterone is related to both handedness and degree of linguistic lateralization in normal womenPsychoneuroendocrinology28274287CrossRefPubMedGoogle Scholar
  12. Geschwind, N, Behan, P. 1982Left-handedness: Association with immune disease, migraine, and development learning disorderProc. Natl. Acad. Sci. USA7950975100PubMedGoogle Scholar
  13. Geschwind, N., Galaburda, A. M. 1987Cerebral LateralizationMIT PressCambridge, MAGoogle Scholar
  14. Giovannucci, E., Stampfer, M. J., Krithivas, K., Brown, M., Brufsky, A., Talcott, J., Hennekens, C. H., Kantoff, P. W. 1997The CAG repeat within the androgen receptor gene and its relationship to prostate cancerProc. Natl. Acad. Sci. USA9433203323CrossRefPubMedGoogle Scholar
  15. Grimshaw, G., Bryden, M. P., Finegan, J. K. 1995Relations between prenatal testosterone and cerebral lateralization in childrenNeuropsychology96879CrossRefGoogle Scholar
  16. Haiman, C. A., Brown, M., Hankinson, S. E., Spiegelman, D., Colditz, G. A., Willett, W. C., Kantoff, P. W., Hunter, D. J. 2002The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses′ Health StudyCancer Res6210451049PubMedGoogle Scholar
  17. Hammond, J., Le, Q., Goodyer, C., Gelfand, M., Trifiro, M., LeBlanc, A. 2001Testosterone-mediated neuroprotection through the androgen receptor in human primary neuronsJ.␣Neurochem.7713191326PubMedGoogle Scholar
  18. Hardy, D. O., Scher, H. I., Bogenreider, T., Sabbatini, P., Zhang, Z.-F., Nanus, D. M., Catterall, J. F. 1996Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onsetJ. Clin. Endocrinol. Metab.8144004405CrossRefPubMedGoogle Scholar
  19. Hauck, J., Dewey, D. 2001Hand preference and motor functioning in children with autismJ. Autism Dev. Disord.31265277CrossRefPubMedGoogle Scholar
  20. Hepper, P., McCartney, G., Shannon, E. 1998Lateralised behaviour in first trimester human foetusesNeuropsychologia36521534CrossRefGoogle Scholar
  21. Hepper, P., Shahidullah, S., White, R. 1990Handedness in the human foetusNeuropsychologia2911071111Google Scholar
  22. Hickey, T., Chandy, A., Norman, R. J. 2002The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndromeJ. Clin. Endocrinol. Metab.87161165CrossRefPubMedGoogle Scholar
  23. Irvine, R. A., Yu, M. C., Ross, R. K., Coetzee, G. A. 1995The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancerCancer Res.5519371940PubMedGoogle Scholar
  24. Klar, A. J. S. 1999Genetic models for handedness, brain lateralization, schizophrenia, and manic-depresssionSchizophrenia Res.39207218Google Scholar
  25. Kramer, M. A., Albrecht, S., Miller, R. A. 1985aHandedness and the laterality of breast cancer in womenNurs. Res.34333337Google Scholar
  26. Kramer, M. A., Albrecht, S., Miller, R. A. 1985Higher frequency of left-breast cancer: a possible explanationPercept Mot Skills61583588PubMedGoogle Scholar
  27. Krithivas, K., Yurgalevitvh, S. M., Mohr, B. A., Wilcox, C. J., Batter, S. J., Brown, M., Longcope, C., McKinlay, J. B., Kantoff, P. W. 1999Evidence that the CAG repeat in the androgen receptor gene is associated with the age related decline in serum androgen levels in menJ. Endocrinol.162137142CrossRefPubMedGoogle Scholar
  28. La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., Fischbeck, K. H. 1991Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophyNature3527779PubMedGoogle Scholar
  29. Laval, S., Dann, J., Butler, R., Loftus, J., Rue, J., Leask, S., Bass, N., Comazzi, M., Vita, A., Nanko, S., Shaw, S., Peterson, P., Shields, G., Smith, A., Stewart, J., DeLisi, L., Crow, T. 1998Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosomeAm. J. Med. Genet.7420427Google Scholar
  30. Lillie, E. O., Bernstein, L., Ursin, G. 2003The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancerBreast Cancer Res.5164173CrossRefPubMedGoogle Scholar
  31. London, W. P. 1992Reversed cerebral asymmetry and breast cancerLancet33910551056PubMedGoogle Scholar
  32. London, W. P., Albrecht, S. A. 1991Breast cancer and cerebral lateralityPercept Mot Skills72112114PubMedGoogle Scholar
  33. McAbee, M. D., Doncarlos, L. L. 1999Estrogen, but not androgens, regulates androgen receptor messenger ribonucleic acid expression in the developing male rat forebrainEndocrinology14036743681PubMedGoogle Scholar
  34. McManus, C. 2002Right Hand, Left Hand: The origins of asymmetry in Brains, Bodies, Atoms and CulturesWeidenfeld & NicolsonLondonGoogle Scholar
  35. McManus, I. C. 1985Handedness, language dominance and aphasia: A genetic modelPsychol. Med. Monographs Supplement81140Google Scholar
  36. McManus, I. C. 1992Reversed cerebral asymmetry and breast cancerLancet3391055CrossRefPubMedGoogle Scholar
  37. Medland, S. E., Wright, M. J., Geffen, G. M., Hay, D. A., Levy, F., Martin, N., Duffy, D. 2003Special twin environments and their effects on the handedness of twins and their siblingsTwin Res.6119130CrossRefPubMedGoogle Scholar
  38. Moffat, S. D., Hampson, E. 1996Salivary testosterone levels in left-and right-handed adultsNeuropsychologia34225233CrossRefPubMedGoogle Scholar
  39. Natsopoulos, D., Koutselini, M., Kiosseoglou, G., Koundouris, F. 2002Differences in language performance in variations of lateralizationBrain Lang.82223240CrossRefPubMedGoogle Scholar
  40. Neale, M. C., Boker, S. M., Xie, G., and Maes, H. H. (2002). Mx: Statistical Modeling (6th Edition ed.). VCU Box 900126, Richmond, VA 23298 http://www.vcu.edu/mx/:Department of Psychiatry.Google Scholar
  41. Newman, H. H. 1928Studies of Human Twins II. Asymmetry reversal of mirrorimaging in identical twinsBiol. Bull.55298315Google Scholar
  42. Piccioni, F., Pinton, P., Simeoni, S., Pozzi, P., Fascio, U., Vismara, G., Martini, L., Rizzuto, R., Poletti, A. 2002Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processesFASEB J.1614181420PubMedGoogle Scholar
  43. Pujol, J., Deus, J., Losilla, J. M., Capdevila, A. 1999Cerebral lateralization of language in normal left handed people studies by functional MRINeurology5210381043PubMedGoogle Scholar
  44. Sandson, T. A., Wen, P. Y., LeMay, M. 1992Reversed cerebral asymmetry in women with breast cancerLancet339523524CrossRefPubMedGoogle Scholar
  45. Satz, P., Green, M. F. 1999Atypical handedness in schizophrenia: some methodological and theoretical issuesSchizophrenia Bull.256378Google Scholar
  46. Satz, P., Orsini, D. L., Saslow, E., Henry, R. 1985The pathological left-handedness syndromeBrain Cognition42746Google Scholar
  47. Shaw, J., Claridge, G., Clark, K. 2001Schizotpy and the shift from dextrality: a study of handedness in a large non-clinical sampleSchizophrenia Res.50181189Google Scholar
  48. Spurdle, A. B., Webb, P. M., Chen, X., Martin, N. G., Giles, G. G., Hopper, J. L., Chenevix-Trench, G. 2000Androgen receptor exon 1 CAG repeat length and risk of ovarian cancerInt. J. Cancer87637643CrossRefPubMedGoogle Scholar
  49. Tan, U. 1990aRelation of testosterone and hand preference in right-handed young adults to sex and familial sinistralityInt. J. Neurosci.53157165Google Scholar
  50. Tan, U. 1990bRelationship of testosterone and nonverbal intelligence to hand preference and hand skill in right-handed young adultsInt. J. Neurosci.54267276Google Scholar
  51. Titus-Ernstoff, L., Newcomb, P. A., Egan, K. M., Baron, J. A., Greenberg, E. R., Trichopoulos, D., Willett, W. C., Stampfer, M. J. 2000Left-handedness in relation to breast cancer risk in postmenopausal womenEpidemiology11181184CrossRefPubMedGoogle Scholar
  52. Tut, T., Ghadessy, F., Trifiro, M., Pinsky, L., Yong, E. 1997Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertilityJ. Clin. Endocrinol. Metab.8237773782CrossRefPubMedGoogle Scholar
  53. Westberg, L., Baghael, F., Rosmond, R., Hellstrand, M., Landén, M., Jansson, M., Holm, G., Björntorp, P., Eriksson, E. 2001Polymorphisms of the androgen receptor gene and estrogen receptor beta gene are associated with androgen levels in womenJ. Clin. Endocrinol. Metab.8625622568CrossRefPubMedGoogle Scholar
  54. Witelson, S. F., Nowakowski, R. S. 1991Left out axons make men right: A hypothesis for the origin of handedness and functional asymmetryNeuropsychologia29327333CrossRefPubMedGoogle Scholar
  55. Wright, M., De Geus, E., Ando, J., Luciano, M., Posthuma, D., Ono, Y., Hansell, N., Van Baal, C., Hiraishi, K., Toshikazu, H., Smith, G., Geffen, G., Geffen, L., Kanba, S., Miyake, A., Martin, N., Boomsma, D. 2001Genetics of Cognition: Outline of a Collaborative Twin StudyTwin Res.44856CrossRefPubMedGoogle Scholar
  56. Yeap, B. B., Wilce, J. A., Leedman, P. J. 2004The androgen receptor mRNABioessays26672682CrossRefPubMedGoogle Scholar
  57. Zhu, G., Duffy, D. L., Eldridge, A., Grace, M., Mayne, C., O′Gorman, L., Aitken, J. F., Neale, M. C., Hayward, N. K., Green, A. C., Martin, N. G. 1999A major quantitative-trait locus for mole density is linked to the familial melanoma gene CDKN2A: a maximum-likelihood combined linkage and association analysis in twins and their sibsAm. J. Human Genet.65483492Google Scholar
  58. Zhu, G., Evans, D. M., Duffy, D. L., Montgomery, G. W., Medland, S. E., Gillespie, N. A., Ewen, K. R., Jewell, M., Liew, Y. W., Hayward, N. K., Sturm, R. A., Trent, J. M., Martin, N. G. 2004A genome scan for eye colour in 502 twin families: most variation is due to a QTL on chromosome 15qTwin Res.7197210CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Sarah E. Medland
    • 1
    • 2
  • David L. Duffy
    • 1
  • Amanda B. Spurdle
    • 1
  • Margaret J. Wright
    • 1
  • Gina M. Geffen
    • 2
  • Grant W. Montgomery
    • 1
  • Nicholas G. Martin
    • 1
  1. 1.Queensland Institute of Medical ResearchPO Royal Brisbane HospitalBrisbaneAustralia
  2. 2.Cognitive Psychophysiology LaboratoryUniversity of QueenslandAustralia

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