Skip to main content
SpringerLink
Log in

Examination of the Effect of the Polymorphic CGG Repeat in the FMR1 Gene on Cognitive Performance

  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

A CGG repeat sequence located in the 5′ untranslated region of the FMR1 gene is polymorphic with respect to size and stability of the repeat during parent-offspring transmission. When expanded to over 200 repeats, the gene is hypermethylated and silenced, leading to fragile X syndrome (FXS). Recently, alleles with large unmethylated repeat tracts (premutations) have been associated with ovarian failure and a late-onset tremor/ataxia syndrome, symptoms unrelated to FXS. To further investigate the phenotype consequence of high repeat alleles, we have analyzed Wechsler adult intelligence scales-III (WAIS-III) measures on 66 males and 217 females with a wide range of repeat sizes. Among females only, we found that FMR1 repeat size and transcript level significantly explained approximately 4% of the variance in the Verbal IQ summary measure, suggesting that this polymorphism is one of many factors that influence variation in cognitive performance. Because of the well established association of increasing repeat size with decreasing age at menopause, we also investigated the reproductive stage and use of hormone replacement therapy (HRT) as a covariate to model verbal intelligence quotient (VIQ). We found that it explained an additional 5% of the variance in VIQ, but did not interact with FMR1 repeat and transcript level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • E. G. Allen W. He M. Yadav-Shah S. L. Sherman (2004) ArticleTitleA study of the distributional characteristics of FMR1 transcript levels in 238 individuals Hum. Genet. 114 IssueID5 439–447 Occurrence Handle1:CAS:528:DC%2BD2cXisFSrurY%3D Occurrence Handle14758538

    CAS  PubMed  Google Scholar 

  • D. J. Allingham-Hawkins C. A. Brown R. Babul D. Chitayat K. Krekewich T. Humphries et al. (1996) ArticleTitleTissue-specific methylation differences and cognitive function in fragile X premutation females Am. J. Med. Genet. 64 IssueID2 329–333 Occurrence Handle1:STN:280:ByiD3c7gsVE%3D Occurrence Handle8844075

    CAS  PubMed  Google Scholar 

  • C. T. Ashley SuffixJr. K. D. Wilkinson D. Reines S. T Warren (1993) ArticleTitleFMR1 protein: conserved RNP family domains and selective RNA binding Science 262 IssueID5133 563–566 Occurrence Handle1:CAS:528:DyaK3sXms1Cqtr0%3D Occurrence Handle7692601

    CAS  PubMed  Google Scholar 

  • E. Barrett-Connor D. Kritz-Silverstein (1993) ArticleTitleEstrogen replacement therapy and cognitive function in older women Jama 269 IssueID20 2637–2641 Occurrence Handle1:CAS:528:DyaK3sXkvVKmsrc%3D Occurrence Handle8487446

    CAS  PubMed  Google Scholar 

  • W. T. Brown G. E. Houck SuffixJr. A. Jeziorowska F. N. Levinson X. Ding C. Dobkin et al. (1993) ArticleTitleRapid fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test Jama 270 IssueID13 1569–1575 Occurrence Handle1:CAS:528:DyaK2cXisVCgtg%3D%3D Occurrence Handle8371467

    CAS  PubMed  Google Scholar 

  • J. A. Brunberg S. Jacquemont R. J. Hagerman E. M. Berry-Kravis J. Grigsby M. A. Leehey et al. (2002) ArticleTitleFragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction AJNR Am. J. Neuroradiol. 23 IssueID10 1757–1766 Occurrence Handle12427636

    PubMed  Google Scholar 

  • D. C. Crawford J. M. Acuna S. L. Sherman (2001) ArticleTitleFMR1 and the fragile X syndrome: human genome epidemiology review Genet. Med. 3 IssueID5 359–371 Occurrence Handle1:CAS:528:DC%2BD3MXntlaltrc%3D Occurrence Handle11545690

    CAS  PubMed  Google Scholar 

  • D. C. Crawford K. L. Meadows J. L. Newman L. F. Taft D. L. Pettay L. B. Gold et al. (1999) ArticleTitlePrevalence and phenotype consequence of FRAXA and FRAXE alleles in a large, ethnically diverse, special education-needs population Am. J. Hum. Genet. 64 IssueID2 495–507 Occurrence Handle1:STN:280:DyaK1M7jvVKlsw%3D%3D Occurrence Handle9973286

    CAS  PubMed  Google Scholar 

  • D. C. Crawford K. L. Meadows J. L. Newman L. F. Taft E. Scott M. Leslie et al. (2002) ArticleTitlePrevalence of the fragile X syndrome in African-Americans Am. J. Med. Genet. 110 IssueID3 226–233 Occurrence Handle12116230

    PubMed  Google Scholar 

  • D. C. Crawford C. E. Schwartz K. L. Meadows J. L. Newman L. F. Taft C. Gunter et al. (2000) ArticleTitleSurvey of the fragile X syndrome CGG repeat and the short-tandem-repeat and single-nucleotide-polymorphism haplotypes in an African American population Am. J. Hum. Genet. 66 IssueID2 480–493 Occurrence Handle1:CAS:528:DC%2BD3cXitFyitrk%3D Occurrence Handle10677308

    CAS  PubMed  Google Scholar 

  • A. K. Farrag E. M. Khedr H. Abdel-Aleem T. A Rageh (2002) ArticleTitleEffect of surgical menopause on cognitive functions Dement. Geriatr. Cogn. Disord. 13 IssueID3 193–198 Occurrence Handle1:CAS:528:DC%2BD38XhvVSksL4%3D Occurrence Handle11893842

    CAS  PubMed  Google Scholar 

  • P. Franke M. Leboyer M. Gansicke O. Weiffenbach V. Biancalana P. Cornillet-Lefebre et al. (1998) ArticleTitleGenotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1 Psychiatry. Res. 80 IssueID2 113–127 Occurrence Handle1:STN:280:DyaK1cvisFKrtw%3D%3D Occurrence Handle9754690

    CAS  PubMed  Google Scholar 

  • P. Franke M. Leboyer J. Hardt E. Sohne O. Weiffenbach V. V. Biancalana et al. (1999) ArticleTitleNeuropsychological profiles of FMR-1 premutation and full-mutation carrier females Psychiatry. Res. 87 IssueID2–3 223–231 Occurrence Handle10579555

    PubMed  Google Scholar 

  • Y. H. Fu D. P. Kuhl A. Pizzuti M. Pieretti J. S. Sutcliffe S. Richards et al. (1991) ArticleTitleVariation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox Cell 67 IssueID6 1047–1058 Occurrence Handle10.1016/0092-8674(91)90283-5 Occurrence Handle1:CAS:528:DyaK38XhtVekurk%3D Occurrence Handle1760838

    Article  CAS  PubMed  Google Scholar 

  • C. M. Greco R. J. Hagerman F. Tassone A. E. Chudley M. R. Del Bigio S. Jacquemont et al. (2002) ArticleTitleNeuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers Brain 125 IssueIDPt 8 1760–1771 Occurrence Handle10.1093/brain/awf184 Occurrence Handle1:STN:280:DC%2BD38vjt1CqtQ%3D%3D Occurrence Handle12135967

    Article  CAS  PubMed  Google Scholar 

  • P. J. Hagerman R. J. Hagerman (2004) ArticleTitleThe fragile-X premutation: a maturing perspective Am. J. Hum. Genet. 74 IssueID5 805–816 Occurrence Handle1:CAS:528:DC%2BD2cXjvVeis7w%3D Occurrence Handle15052536

    CAS  PubMed  Google Scholar 

  • R. J. Hagerman M. Leehey W. Heinrichs F. Tassone R. Wilson J. Hills et al. (2001) ArticleTitleIntention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X Neurology 57 IssueID1 127–130 Occurrence Handle1:STN:280:DC%2BD3MzptFejug%3D%3D Occurrence Handle11445641

    CAS  PubMed  Google Scholar 

  • P. Jin D. C. Zarnescu F. Zhang C. E. Pearson J. C. Lucchesi K. Moses et al. (2003) ArticleTitleRNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila Neuron 39 IssueID5 739–747 Occurrence Handle10.1016/S0896-6273(03)00533-6 Occurrence Handle1:CAS:528:DC%2BD3sXnt1Wku74%3D Occurrence Handle12948442

    Article  CAS  PubMed  Google Scholar 

  • C. Johnston S. Eliez J. Dyer-Friedman D. Hessl B. Glaser C. Blasey et al. (2001) ArticleTitleNeurobehavioral phenotype in carriers of the fragile X premutation Am. J. Med. Genet. 103 IssueID4 314–319 Occurrence Handle10.1002/ajmg.1561 Occurrence Handle1:STN:280:DC%2BD3MnpsFymsA%3D%3D Occurrence Handle11746012

    Article  CAS  PubMed  Google Scholar 

  • D. L. Kampen B. B. Sherwin (1994) ArticleTitleEstrogen use and verbal memory in healthy postmenopausal women Obstet. Gynecol. 83 IssueID6 979–983 Occurrence Handle1:STN:280:ByuB2cjotlY%3D Occurrence Handle8190445

    CAS  PubMed  Google Scholar 

  • W. E. Kaufmann M. T. Abrams W. Chen A. L. Reiss (1999) ArticleTitleGenotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome Am. J. Med. Genet. 83 IssueID4 286–295 Occurrence Handle10.1002/(SICI)1096-8628(19990402)83:4<286::AID-AJMG10>3.0.CO;2-H Occurrence Handle1:STN:280:DyaK1M3it1yntg%3D%3D Occurrence Handle10208163

    Article  CAS  PubMed  Google Scholar 

  • D. Z. Loesch Q. M. Bui J. Grigsby E. Butler J. Epstein R. M. Huggins et al. (2003a) ArticleTitleEffect of the fragile X status categories and the fragile X mental retardation protein levels on executive functioning in males and females with fragile X Neuropsychology 17 IssueID4 646–657 Occurrence Handle10.1037/0894-4105.17.4.646

    Article  Google Scholar 

  • D. Z. Loesch D. A. Hay J. Mulley (1994) ArticleTitleTransmitting males and carrier females in fragile X–revisited Am. J. Med. Genet. 51 IssueID4 392–399 Occurrence Handle10.1002/ajmg.1320510418 Occurrence Handle1:STN:280:ByqD38bltlc%3D Occurrence Handle7943005

    Article  CAS  PubMed  Google Scholar 

  • D. Z. Loesch R. M. Huggins Q. M. Bui J. L. Epstein A. K. Taylor R. J. Hagerman (2002) ArticleTitleEffect of the deficits of fragile X mental retardation protein on cognitive status of fragile x males and females assessed by robust pedigree analysis J. Dev. Behav. Pediatr. 23 IssueID6 416–423 Occurrence Handle12476071

    PubMed  Google Scholar 

  • D. Z. Loesch R. M. Huggins Q. M. Bui A. K. Taylor R. J. Hagerman (2003b) ArticleTitleRelationship of deficits of FMR1 gene specific protein with physical phenotype of fragile X males and females in pedigrees: a new perspective Am. J. Med. Genet. 118A IssueID(2 127–134

    Google Scholar 

  • D. Z. Loesch R. M. Huggins Q. M. Bui A. K. Taylor C. Pratt J. Epstein et al. (2003c) ArticleTitleEffect of fragile X status categories and FMRP deficits on cognitive profiles estimated by robust pedigree analysis Am. J. Med. Genet. 122A IssueID(1 13–23

    Google Scholar 

  • J. MacNaughton M. Banah P. McCloud J. Hee H Burger (1992) ArticleTitleAge related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age Clin. Endocrinol. (Oxf) 36 IssueID4 339–345 Occurrence Handle1:CAS:528:DyaK38XksVSrt78%3D

    CAS  Google Scholar 

  • M. M. Mazzocco B. F. Pennington R. J. Hagerman (1993) ArticleTitleThe neurocognitive phenotype of female carriers of fragile X: additional evidence for specificity J. Dev. Behav. Pediatr. 14 IssueID5 328–335 Occurrence Handle1:STN:280:ByuD2srms1I%3D Occurrence Handle8254064

    CAS  PubMed  Google Scholar 

  • K. L. Meadows D. Pettay J. Newman J. Hersey A. E. Ashley S. L. Sherman (1996) ArticleTitleSurvey of the fragile X syndrome and the fragile X E syndrome in a special education needs population Am. J. Med. Genet. 64 IssueID2 428–433 Occurrence Handle1:STN:280:ByiD3c7gs1w%3D Occurrence Handle8844098

    CAS  PubMed  Google Scholar 

  • S. L. Nolin W. T. Brown A. Glicksman G. E. Houck SuffixJr. A. D. Gargano A. Sullivan et al. (2003) ArticleTitleExpansion of the fragile X CGG repeat in females with premutation or intermediate alleles Am. J. Hum. Genet. 72 IssueID2 454–464 Occurrence Handle1:CAS:528:DC%2BD3sXht12rtLw%3D Occurrence Handle12529854

    CAS  PubMed  Google Scholar 

  • C. E. Pearson R. R. Sinden (1996) ArticleTitleAlternative structures in duplex DNA formed within the trinucleotide repeats of the myotonic dystrophy and fragile X loci Biochemistry 35 IssueID15 5041–5053 Occurrence Handle1:CAS:528:DyaK28XhvVCls7c%3D Occurrence Handle8664297

    CAS  PubMed  Google Scholar 

  • R. Plomin G. E. McClearn D. L. Smith S. Vignetti M. J. Chorney K. Chorney et al. (1994) ArticleTitleDNA markers associated with high versus low IQ: the IQ quantitative trait loci (QTL) project Behav. Genet. 24 IssueID2 107–118 Occurrence Handle1:STN:280:ByuB1MnjsFQ%3D Occurrence Handle8024528

    CAS  PubMed  Google Scholar 

  • A. L. Reiss L. Freund M. T. Abrams C. Boehm H. Kazazian (1993) ArticleTitleNeurobehavioral effects of the fragile X premutation in adult women: a controlled study Am. J. Hum. Genet. 52 IssueID5 884–894 Occurrence Handle1:STN:280:ByyB2MngslQ%3D Occurrence Handle8488838

    CAS  PubMed  Google Scholar 

  • D. Robinson L. Friedman R. Marcus J. Tinklenberg J. Yesavage (1994) ArticleTitleEstrogen replacement therapy and memory in older women J. Am. Geriatr. Soc. 42 919–922 Occurrence Handle1:STN:280:ByuA2c3mvVE%3D Occurrence Handle8064097

    CAS  PubMed  Google Scholar 

  • J. L. Ross G. A. Stefanatos H. Kushner C. Bondy L. Nelson A. Zinn et al. (2004) ArticleTitleThe effect of genetic differences and ovarian failure: intact cognitive function in adult women with premature ovarian failure versus turner syndrome J. Clin. Endocrinol. Metab. 89 IssueID4 1817–1822 Occurrence Handle1:CAS:528:DC%2BD2cXjt1elt7s%3D Occurrence Handle15070950

    CAS  PubMed  Google Scholar 

  • S. L. Sherman (2000) ArticleTitlePremature ovarian failure in the fragile X syndrome Am. J. Med. Genet. 97 IssueID3 189–194 Occurrence Handle1:STN:280:DC%2BD3Mzpsl2gug%3D%3D Occurrence Handle11449487

    CAS  PubMed  Google Scholar 

  • B. B. Sherwin (2003) ArticleTitleEstrogen and cognitive functioning in women Endocr. Rev. 24 IssueID2 133–151 Occurrence Handle1:CAS:528:DC%2BD3sXjsFyltL8%3D Occurrence Handle12700177

    CAS  PubMed  Google Scholar 

  • J. Steyaert M. Borghgraef J. P. Fryns (1994) ArticleTitleApparently enhanced visual information processing in female fragile X carriers: preliminary findings Am. J. Med. Genet. 51 IssueID4 374–377 Occurrence Handle1:STN:280:ByqD38bltlQ%3D Occurrence Handle7943002

    CAS  PubMed  Google Scholar 

  • A. K. Sullivan D. C. Crawford E. H. Scott M. L. Leslie S. L. Sherman (2002) ArticleTitlePaternally transmitted FMR1 alleles are less stable than maternally transmitted alleles in the common and intermediate size range Am. J. Hum. Genet. 70 IssueID6 1532–1544 Occurrence Handle1:CAS:528:DC%2BD38Xkt1SqsLo%3D Occurrence Handle11992259

    CAS  PubMed  Google Scholar 

  • Sullivan, A. K., Marcus, M., Epstein, M. P., Allen, E. G., Anido, A. E., Brown, J., Edwards, I., Harkreader, K., He, W., Leslie, M. L., Novak, G., Paquin, J. J., Scott, E. H., Shubeck, L. J., Sowemimo, D. J., Taft, L., Yadav-Shah, M., and Sherman, S.L. (2004). Association of FMR1 repeat size with ovarian dysfunction. Human Reproduct.. submitted/under revision

  • R. Willemsen M. Hoogeveen-Westerveld S. Reis J. Holstege L. A. Severijnen I. M. Nieuwenhuizen et al. (2003) ArticleTitleThe FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome Hum. Mol. Genet. 12 IssueID9 949–959 Occurrence Handle1:CAS:528:DC%2BD3sXkt1Kku78%3D Occurrence Handle12700164

    CAS  PubMed  Google Scholar 

  • S. A. Youings A. Murray N. Dennis S. Ennis C. Lewis N. McKechnie et al. (2000) ArticleTitleFRAXA and FRAXE: the results of a five year survey J. Med. Genet. 37 IssueID6 415–421 Occurrence Handle1:CAS:528:DC%2BD3cXltFSisbg%3D Occurrence Handle10851251

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Emory University, Atlanta, GA, 30322, USA

    Emily Graves Allen, Stephanie Sherman, Ann Abramowitz, Mary Leslie, Gloria Novak, Michele Rusin, Elizabeth Scott & Richard Letz

Authors
  1. Emily Graves Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephanie Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann Abramowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Leslie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gloria Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michele Rusin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elizabeth Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Richard Letz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephanie Sherman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Allen, E.G., Sherman, S., Abramowitz, A. et al. Examination of the Effect of the Polymorphic CGG Repeat in the FMR1 Gene on Cognitive Performance. Behav Genet 35, 435–445 (2005). https://doi.org/10.1007/s10519-005-2792-4

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-005-2792-4

Keywords

Search

Navigation