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Genetic Variation in Ataxia Gene ATXN7 Influences Cerebellar Grey Matter Volume in Healthy Adults

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Abstract

An increasing number of candidate genes for common and rare brain disorders are discovered, but the mechanism of action through which these genes cause disease is often still unclear. Some of the genetic factors known to increase the risk for common brain disorders affect brain structure, even in healthy individuals, and therefore possibly have a role in the normal development of specific brain regions. In this study, we explored this principle for a group of rare brain disorders, the spinocerebellar ataxias (SCAs). As a proof of concept, we investigated whether genetic variation in a gene known to cause a polyglutamine-expansion SCA is associated with cerebellar volume in healthy adults. The functional single nucleotide polymorphism (SNP) rs3774729 located in ATXN7 was selected as the variant of interest. Cerebellar grey matter volume was determined using volumetry on magnetic resonance imaging data in a discovery sample scanned at 1.5 T (n = 680) and a replication sample scanned at 3 T (n = 683), both consisting of healthy adults aged 18 to 35 years. The volumes were compared as a function of the presence of the minor allele of SNP rs3774729, which was associated with significantly smaller cerebellar grey matter volume in both the discovery and replication sample (p = 0.033 and p = 0.024, respectively). Our results demonstrate that a common genetic variant in the ataxia-causing gene ATXN7 influences cerebellar grey matter volume in healthy young adults. This finding may also imply that genes associated with cerebellar volume in healthy subjects are valid candidates for causing or modifying ataxia.

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References

  1. Barnes A, Isohanni M, Barnett JH, Pietiläinen O, Veijola J, Miettunen J, et al. Neuregulin-1 genotype is associated with structural differences in the normal human brain. NeuroImage. 2012;59:2057–61.

    Article  PubMed  CAS  Google Scholar 

  2. Bueller JA, Aftab M, Sen S, Gomez-Hassan D, Burmeister M, Zubieta JK. BDNF Val66Met allele is associated with reduced hippocampal volume in healthy subjects. Biol Psychiatry. 2006;59:812–5.

    Article  PubMed  CAS  Google Scholar 

  3. Inoue H, Yamasue H, Tochigi M, Abe O, Liu X, Kawamura Y. Association between the oxytocin receptor gene and amygdalar volume in healthy adults. Biol Psychiatry. 2010;68:1066–72.

    Article  PubMed  CAS  Google Scholar 

  4. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE, et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci. 2004;24:10099–102.

    Article  PubMed  CAS  Google Scholar 

  5. Bralten J, Franke B, Arias-Vásquez A, Heister A, Brunner HG, Fernández G, et al. CR1 genotype is associated with entorhinal cortex volume in young healthy adults. Neurobiol Aging. 2011;32:2106e7–2106e11.

    Article  Google Scholar 

  6. Bralten J, Arias-Vásquez A, Makkinje R, Veltman JA, Brunner HG, Fernández G. Association of the Alzheimer’s gene SORL1 with hippocampal volume in young, healthy adults. Am J Psychiatry. 2011;168:1083–9.

    Article  PubMed  Google Scholar 

  7. Finsterer J. Ataxias with autosomal, X-chromosomal or maternal inheritance. Can J Neurol Sci. 2009;36:409–28.

    PubMed  Google Scholar 

  8. Klockgether T. Sporadic ataxia with adult onset: classification and diagnostic criteria. Lancet Neurol. 2010;9:94–104.

    Article  PubMed  CAS  Google Scholar 

  9. Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9:94–104.

    Article  Google Scholar 

  10. Vermeer S, van de Warrenburg BP, Willemsen MA, Cluitmans M, Scheffer H, Kremer BP, et al. Autosomal recessive cerebellar ataxias: the current state of affairs. J Med Genet. 2011;48:651–9.

    Article  PubMed  CAS  Google Scholar 

  11. La Spada AR, Taylor JP. Polyglutamines placed into context. Neuron. 2003;38:681–4.

    Article  PubMed  Google Scholar 

  12. Duvick L, Barnes J, Ebner B, Agrawal S, Andresen M, Lim J, et al. SCA1-like disease in mice expressing wild-type ataxin-1 with a serine to aspartic acid replacement at residue 776. Neuron. 2010;67:929–35.

    Article  PubMed  CAS  Google Scholar 

  13. Lim J, Crespo-Barreto J, Jafar-Nejad P, Bowman AB, Richman R, Hill DE. Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature. 2008;452:713–8.

    Article  PubMed  CAS  Google Scholar 

  14. Maltecca F, Aghaie A, Schroeder DG, Cassina L, Taylor BA, Phillips SJ, et al. The mitochondrial protease AFG3L2 is essential for axonal development. J Neurosci. 2008;28:2827–36.

    Article  PubMed  CAS  Google Scholar 

  15. Franke B, Vasquez AA, Veltman JA, Brunner HG, Rijpkema M, Fernández G. Genetic variation in CACNA1C, a gene associated with bipolar disorder, influences brainstem rather than grey matter volume in healthy individuals. Biol Psychiatry. 2010;68:586–8.

    Article  PubMed  CAS  Google Scholar 

  16. Jovicich J, Czanner S, Han X, Salat D, van der Kouwe A, Quinn B, et al. MRI-derived measurements of human subcortical, ventricular and intracranial brain volumes: reliability effects of scan sessions, acquisition sequences, data analyses, scanner upgrade, scanner vendors and field strengths. NeuroImage. 2009;46:177–92.

    Article  PubMed  Google Scholar 

  17. Ashburner J, Friston KJ. Voxel-based morphometry—the methods. NeuroImage. 2000;11:805–21.

    Article  PubMed  CAS  Google Scholar 

  18. Cuadra MB, Cammoun L, Butz T, Cuisenaire O, Thiran JP. Comparison and validation of tissue modelization and statistical classification methods in T1-weighted MR brain images. IEEE Trans Med Imaging. 2005;24:1548–65.

    Article  PubMed  Google Scholar 

  19. Shattuck DW, Mirza M, Adisetiyo V, Hojatkashani C, Salamon G, Narr KL, et al. Construction of a 3D probabilistic atlas of human cortical structures. NeuroImage. 2008;39:1064–80.

    Article  PubMed  Google Scholar 

  20. Yamada M, Sato T, Tsuji S, Takahashi H. CAG repeat disorder models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115:71–86.

    Article  PubMed  CAS  Google Scholar 

  21. Helmlinger D, Hardy S, Sasorith S, Klein F, Robert F, Weber C. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum Mol Genet. 2004;13:1257–65.

    Article  PubMed  CAS  Google Scholar 

  22. Chou AH, Chen CY, Chen SY, Chen WJ, Chen YL, Weng YS, et al. Polyglutamine-expanded ataxin-7 causes cerebellar dysfunction by inducing transcriptional dysregulation. Neurochem Int. 2010;56:329–39.

    Article  PubMed  CAS  Google Scholar 

  23. Garden GA, La Spada AR. Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum. 2008;7:138–49.

    Article  PubMed  CAS  Google Scholar 

  24. Reetz K, Lencer R, Hagenah JM, Gaser C, Tadic V, Walter U, et al. Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17. Cerebellum. 2010;9:210–7.

    Article  PubMed  Google Scholar 

  25. David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nature Genet. 1997;17:65–70.

    Article  PubMed  CAS  Google Scholar 

  26. Monticelli A, Giacchetti M, De Biase I, Pianese L, Turano M, Pandolfo M, et al. New clues on the origin of the Friedreich ataxia expanded alleles from the analysis of new polymorphisms closely linked to the mutation. Hum Genet. 2004;114:458–63.

    Article  PubMed  CAS  Google Scholar 

  27. van de Warrenburg BP, Hendriks H, Dürr A, van Zuijlen MC, Stevanin G, Camuzat A, et al. Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort. Ann Neurol. 2005;57:505–12.

    Article  PubMed  Google Scholar 

  28. Mori E, Hirono N, Yamashita H, Imamura T, Ikejiri Y, Ikeda M, et al. Premorbid brain size as a determinant of reserve capacity against intellectual decline in Alzheimer’s disease. Am J Psychiatry. 1997;154:18–24.

    PubMed  CAS  Google Scholar 

  29. Mortimer JA, Borenstein AR, Gosche KM, Snowdon DA. Very early detection of Alzheimer neuropathology and the role of brain reserve in modifying its clinical expression. J Geriatr Psychiatry Neurol. 2005;18:218–23.

    Article  PubMed  Google Scholar 

  30. Petrosini L, De Bartolo P, Foti F, Gelfo F, Cutuli D, Leggio MG. On whether the environmental enrichment may provide cognitive and brain reserves. Brain Res Rev. 2009;61:221–39.

    Article  PubMed  Google Scholar 

  31. Canu E, Boccardi M, Ghidoni R, Benussi L, Duchesne S, Testa C, et al. HOXA1 A218G polymorphism is associated with smaller cerebellar volume in healthy humans. Neuroimaging. 2009;19:353–8.

    Article  Google Scholar 

  32. Tan GC, Doke TF, Ashburner J, Wood NW, Frackowiak RS. Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2. NeuroImage. 2010;53:1030–42.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Charlotte D. C. C. van der Heijden & Bart P. van de Warrenburg

  2. Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands

    Mark Rijpkema, Alejandro Arias-Vásquez, Hans Scheffer, Guillen Fernandez, Barbara Franke & Bart P. van de Warrenburg

  3. Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Mark Rijpkema

  4. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Alejandro Arias-Vásquez, Marina Hakobjan, Hans Scheffer & Barbara Franke

  5. Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Barbara Franke

  6. Department of Human Genetics (855), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Barbara Franke

Authors
  1. Charlotte D. C. C. van der Heijden
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  2. Mark Rijpkema
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  3. Alejandro Arias-Vásquez
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  4. Marina Hakobjan
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  5. Hans Scheffer
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  6. Guillen Fernandez
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  7. Barbara Franke
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  8. Bart P. van de Warrenburg
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Correspondence to Barbara Franke.

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van der Heijden, C.D.C.C., Rijpkema, M., Arias-Vásquez, A. et al. Genetic Variation in Ataxia Gene ATXN7 Influences Cerebellar Grey Matter Volume in Healthy Adults. Cerebellum 12, 390–395 (2013). https://doi.org/10.1007/s12311-012-0423-1

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  • DOI: https://doi.org/10.1007/s12311-012-0423-1

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