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First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children

Molecular Psychiatry volume 16, pages 97–107 (2011)Cite this article

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Abstract

Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P=5.14e−08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P=6.71e−08). Both SNPs lie in a region devoid of any protein-coding genes; however, they both show significant association with mRNA-expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks.

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References

  1. Shaywitz SE, Morris R, Shaywitz BA . The education of dyslexic children from childhood to young adulthood. Annu Rev Psychol 2008; 59: 451–475.

    Article  Google Scholar 

  2. Paracchini S, Steer CD, Buckingham LL, Morris AP, Ring S, Scerri T et al. Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population. Am J Psychiatry 2008; 165: 1505–1506.

    Article  Google Scholar 

  3. Galaburda AM, LoTurco J, Ramus F, Fitch RH, Rosen GD . From genes to behaviour in developmental dyslexia. Nat Neurosci 2006; 9: 1213–1217.

    Article  CAS  Google Scholar 

  4. Alonso-Bua B, Diaz F, Ferraces MJ . The contribution of AERPs (MMN and LDN) to studying temporal vs linguistic processing deficits in children with reading difficulties. Int J Psychophysiol 2006; 59: 59–167.

    Article  Google Scholar 

  5. Bonte ML, Blomert L . Developmental dyslexia: ERP correlates of anomalous phonological processing during spoken word recognition. Brain Res Cogn Brain Res 2004; 21: 360–376.

    Article  Google Scholar 

  6. Corbera S, Escera C, Artigas J . Impaired duration mismatch negativity in developmental dyslexia. Neuroreport 2006; 17: 1051–1055.

    Article  Google Scholar 

  7. Korpilahti P . Electrophysiological correlates of auditory perception in normal and language impaired children, Thesis by Korpilahti P University of Turku: Turku, Finland, 1996.

    Google Scholar 

  8. Maurer U, Bucher K, Brem S, Benz R, Kranz F, Schulz E et al. Neurophysiology in preschool improves behavioral prediction of reading ability throughout primary school. Biol Psychiat 2009; 66: 341–348.

    Article  Google Scholar 

  9. Schulte-Körne G, Deimel W, Bartling J, Remschmidt H . Auditory processing and dyslexia: evidence for a specific speech processing deficit. Neuroreport 1998; 9: 337–340.

    Article  Google Scholar 

  10. Schulte-Körne G, Deimel W, Bartling J, Remschmidt H . Speech perception deficit in dyslexic adults as measured by mismatch negativity (MMN). Int J Psychophysiol 2001; 40: 77–87.

    Article  Google Scholar 

  11. Hommet C, Vidal J, Roux S, Blanc R, Barthez MA, De Becque B et al. Topography of syllable change-detection electrophysiological indices in children and adults with reading disabilities. Neuropsychologia 2009; 47: 761–770.

    Article  Google Scholar 

  12. Schulte-Körne G, Deimel W, Bartling J, Remschmidt H . Neurophysiological correlates of word recognition in dyslexia. J Neural Transm 2004; 111: 971–985.

    PubMed  Google Scholar 

  13. Sams M, Paavilainen P, Alho K, Näätänen R . Auditory frequency discrimination and event-related potentials. Electroencephalogr Clin Neurophysiol 1985; 62: 437–448.

    Article  CAS  Google Scholar 

  14. Näätänen R, Lehtokoski A, Lennes M, Cheour M, Huotilainen M, Iivonen A et al. Language-specific phoneme representations revealed by electric and magnetic brain responses. Nature 1997; 385: 432–434.

    Article  Google Scholar 

  15. Light GA, Braff DL . Stability of mismatch negativity deficits and their relationship to functional impairments in chronic schizophrenia. Am J Psychiatry 2005; 162: 1741–1743.

    Article  Google Scholar 

  16. Kathmann N, Frodl-Bauch T, Hegerl U . Stability of the mismatch negativity under different stimulus and attention conditions. Clin Neurophysiol 1999; 110: 317–323.

    Article  CAS  Google Scholar 

  17. Näätänen R, Paavilainen P, Rinne T, Alho K . The mismatch negativity (MMN) in basic research of central auditory processing: a review. Clin Neurophysiol 2007; 118: 2544–2590.

    Article  Google Scholar 

  18. Tiitinen H, May P, Reinikainen K, Näätänen R . Attentive novelty detection in humans is governed by pre-attentive sensory memory. Nature 1994; 372: 90–92.

    Article  CAS  Google Scholar 

  19. Scherg M, Vajsar J, Picton TW . A source analysis of the late human auditory evoked potentials. J Cogn Neurosci 1989; 1: 336–355.

    Article  CAS  Google Scholar 

  20. Jemel B, Achenbach C, Müller BW, Röpcke B, Oades RD . Mismatch negativity results from bilateral asymmetric dipole sources in the frontal and temporal lobes. Brain Topogr 2002; 15: 13–27.

    Article  Google Scholar 

  21. Korpilahti P, Lang L, Aaltonen O . Is there a late-latency mismatch negativity (MMN) component? Electroencephalogr Clin Neurophysiol 1995; 95: 96.

    Article  Google Scholar 

  22. Schulte-Körne G, Deimel W, Bartling J, Remschmidt H . The role of phonological awareness, speech perception, and auditory temporal processing for dyslexia. ECAP Suppl 1999; 8: 28–34.

    Google Scholar 

  23. Schulte-Körne G, Deimel W, Bartling J, Remschmidt H . Pre-attentive processing of auditory patterns in dyslexic human subjects. Neurosci Lett 1999; 276: 41–44.

    Article  Google Scholar 

  24. Maurer U, Bucher K, Brem S, Brandeis D . Altered responses to tone and phoneme mismatch in kindergartners at familial dyslexia risk. Neuroreport 2003; 14: 2245–2250.

    Article  Google Scholar 

  25. Stoodley CJ, Hill PR, Stein JF, Bishop DV . Auditory event-related potentials differ in dyslexics even when auditory psychophysical performance is normal. Brain Res 2006; 1121: 190–199.

    Article  CAS  Google Scholar 

  26. Kraus N, McGee TJ, Carrell TD, Zecker SG, Nicol TG, Koch DB . Auditory neurophysiologic responses and discrimination deficits in children with learning problems. Science 1996; 273: 971–973.

    Article  CAS  Google Scholar 

  27. Lachmann T, Berti S, Kujala T, Schröger E . Diagnostic subgroups of developmental dyslexia have different deficits in neural processing of tones and phonemes. Int J Psychophysiol 2005; 56: 105–120.

    Article  Google Scholar 

  28. Sharma M, Purdy SC, Newall P, Wheldall K, Beaman R, Dillon H . Electrophysiological and behavioural evidence of auditory processing deficits in children with reading disorder. Clin Neurophysiol 2006; 117: 1130–1144.

    Article  CAS  Google Scholar 

  29. Ceponiene R, Yaguchi K, Shestakova A, Alku P, Suominen K, Näätänen R . Sound complexity and ‘speechness’ effects on pre-attentive auditory discrimination in children. Int J Psychophysiol 2002; 43: 199–211.

    Article  Google Scholar 

  30. Molfese VJ, Molfese DL, Modgline AA . Newborn and preschool predictors of second-grade reading scores: an evaluation of categorical and continuous scores. J Learn Disabil 2001; 34: 545–554.

    Article  CAS  Google Scholar 

  31. Guttorm TK, Leppänen PH, Poikkeus AM, Eklund KM, Lyytinen P, Lyytinen H . Brain event-related potentials (ERPs) measured at birth predict later language development in children with and without familial risk for dyslexia. Cortex 2005; 41: 291–303.

    Article  Google Scholar 

  32. van Leeuwen T, Been P, Kuijpers C, Zwarts F, Maassen B, van der Leij A . Mismatch response is absent in 2-month-old infants at risk for dyslexia. Neuroreport 2006; 17: 351–355. Erratum in: Neuroreport 2006 17: 1755.

    Article  Google Scholar 

  33. Jessen F, Fries T, Kucharski C, Nishimura T, Hoenig K, Maier W et al. Amplitude reduction of the mismatch negativity in first-degree relatives of patients with schizophrenia. Neurosci Lett 2001; 309: 185–188.

    Article  CAS  Google Scholar 

  34. Schreiber H, Stolz-Born G, Kornhuber HH, Born J . Event related potential correlates of impaired selective attention in children at high risk for schizophrenia. Biol Psychiat 1992; 32: 634–651.

    Article  CAS  Google Scholar 

  35. Umbricht DS, Bates JA, Lieberman JA, Kane JM, Javitt DC . Electrophysiological indices of automatic and controlled auditory information processing in first-episode, recent-onset and chronic schizophrenia. Biol Psychiat 2006; 59: 762–772.

    Article  Google Scholar 

  36. Hall MH, Schulze K, Rijsdijk F, Picchioni M, Ettinger U, Bramon E et al. Heritability and reliability of P300, P50 and duration mismatch negativity. Behav Genet 2006; 36: 845–857.

    Article  Google Scholar 

  37. Schulte-Körne G, Grimm T, Nöthen MM, Müller-Myhsok B, Chichon S, Vogt IR et al. Evidence for linkage of spelling disability to chromosome 15. Am J Hum Genet 1998; 63: 269–282.

    Article  Google Scholar 

  38. Schulte-Körne G, Deimel W, Remschmidt H . Diagnosis of reading and spelling disorder. Z Kinder Jugendpsychiatr Psychother 2001; 29: 113–116.

    Article  Google Scholar 

  39. Ziegler A, König IR, Deimel W, Plume E, Nöthen MM, Propping P et al. Developmental dyslexia-recurrence risk estimates from a german bi-center study using the single proband sib pair design. Hum Hered 2005; 59: 136–143.

    Article  Google Scholar 

  40. Schumacher J, Anthoni H, Dahdouh F, König IR, Hillmer AM, Kluck N et al. Strong evidence of DCDC2 as a susceptibility gene for dyslexia. Am J Hum Genet 2006; 78: 52–62.

    Article  CAS  Google Scholar 

  41. Unnewehr S, Schneider S, Margraf J . Kinder-DIPS: Diagnostisches Interview bei Psychischen Störungen von Kindern und Jugendlichen. Springer: Berlin, Germany, 1998.

    Google Scholar 

  42. Schulte-Körne G, Ziegler A, Deimel W, Schumacher J, Plume E, Bachmann C et al. Interrelationship and familiality of dyslexia related quantitative measures. Ann Hum Genet 2007; 71: 160–175.

    Article  Google Scholar 

  43. Dixon AL, Liang L, Moffatt MF, Chen W, Heath S, Wong KCC et al. A whole-genome association study of global gene expression. Nat Genet 2007; 39: 1202–1207.

    Article  CAS  Google Scholar 

  44. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S et al. Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Nature 2007; 448: 470–473.

    Article  CAS  Google Scholar 

  45. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, Beazley C et al. Population genomics of human gene expression. Nat Genet 2007; 39: 1217–1224.

    Article  CAS  Google Scholar 

  46. Myers AJ, Gibbs JR, Webster JA, Rohrer K, Zhao A, Marlowe L et al. A survey of genetic human cortical gene expression. Nat Genet 2007; 39: 1494–1499.

    Article  CAS  Google Scholar 

  47. Skol AD, Scott LJ, Abecasis GR, Boehnke M . Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nature 2006; 38: 209–213.

    CAS  Google Scholar 

  48. Papassotiropoulos A, Stephan DA, Huentelman MJ, Hoerndli FJ, Craig DW, Pearson JV et al. Common Kibra alleles are associated with human memory performance. Science 2006; 314: 475–478.

    Article  CAS  Google Scholar 

  49. Vellutino FR, Fletcher JM, Snowling MJ, Scanlon DM . Specific reading disability (dyslexia): what have we learned in the past four decades. J Child Psychol Psyc 2004; 45: 2–40.

    Article  Google Scholar 

  50. Pickering SJ . Working memory in dyslexia. In: Alloway TP, Gathercole SE (eds). Working Memory and Neurodevelopmental Disorders. Psychology Press: Hove, UK, 2006, pp 7–40.

    Google Scholar 

  51. Swanson HL . Working memory and reading disabilities: both phonological and executive processing deficits are important. In: Alloway TP, Gathercole SE (eds). Working Memory and Neurodevelopmental Disorders. Psychological Press: Hove, UK, 2006, pp 59–88.

    Google Scholar 

  52. Maher F, Vannucci SJ, Simpson IA . Glucose transporter proteins in brain. FASEB J 1994; 8: 1003–1011.

    Article  CAS  Google Scholar 

  53. McCall A, Van Bueren AM, Moholt-Siebert M, Cherry NJ, Woodward WR . Immunohistochemical localization of the neuron-specific glucose transporter (GLUT3) to neuropil in adult rat brain. Brain Res 1994; 659: 292–297.

    Article  CAS  Google Scholar 

  54. Mantych GJ, James DE, Chung HD, Devaskar SU . Cellular localization and characterization of Glut 3 glucose transporter isoform in human brain. Endocrinology 1992; 131: 1270–1278.

    Article  CAS  Google Scholar 

  55. Khan JY, Rajakumar RA, McKnight RA, Devaskar UP, Devaskar SU . Developmental regulation of genes mediating murine brain glucose uptake. Am J Physiol Regul Inter Comp Physiol 1999; 276: 892–900.

    Article  Google Scholar 

  56. Aghajanian GK, Bloom FE . The formation of synaptic junctions in developing rat brain: a quantitative electron microscopic study. Brain Res 1967; 6: 716–727.

    Article  CAS  Google Scholar 

  57. Sachs GM, Jacobson M, Caviness Jr VS . Postnatal changes in arborization patterns of murine retinocollicular axons. J Comp Neurol 1986; 246: 395–408.

    Article  CAS  Google Scholar 

  58. Huttenlocher PR . Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res 1979; 163: 195–205.

    Article  CAS  Google Scholar 

  59. Huttenlocher PR, de Courten C . The development of synapses in striate cortex of man. Hum Neurobiol 1987; 6: 1–9.

    CAS  Google Scholar 

  60. Johnston MV . Brain plasticity in paediatric neurology. Eur J Paed Neur 2003; 7: 105–113.

    Article  Google Scholar 

  61. Chugani HT . A critical period of brain development: studies of cerebral glucose utilization with PET. Prev Med 1998; 27: 184–188.

    Article  CAS  Google Scholar 

  62. Deza L, Eidelberg E . Development of cortical electrical activity in the rat. Exp Neurol 1967; 17: 425–438.

    Article  CAS  Google Scholar 

  63. Maher F, Simpson IA . Modulation of expression of glucose transporters, Glut 3 and Glut 1, by potassium and N-methyl-D-aspartate in cultured cerebellar granule neurons. Mol Cell Neurosci 1994; 5: 369–375.

    Article  CAS  Google Scholar 

  64. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT . Mapping determinants of human gene expression by regional and genome-wide association. Nature 2005; 43: 1365–1369.

    Article  Google Scholar 

  65. Spilianakis CG, Lalioti MD, Town T, Lee GR, Flavell RA . Interchromosomal associations between alternatively expressed loci. Nature 2005; 435: 637–645.

    Article  CAS  Google Scholar 

  66. Rajakumar RA, Thamotharan S, Menon RK, Devaskar SU . Sp1 and Sp3 regulate transcriptional activity of the facilitative glucose transporter isoform-3 gene in mammalian neuroblasts and trophoblasts. J Biol Chem 1998; 273: 27474–27483.

    Article  CAS  Google Scholar 

  67. Rajakumar A, Thamotharan S, Raychaudhuri N, Menon RK, Devaskar SU . Trans-activators regulating neuronal glucose transporter isoform-3 gene expression in mammalian neurons. J Biol Chem 2004; 279: 26768–26779.

    Article  CAS  Google Scholar 

  68. Burkhalter J, Fiumelli H, Allaman I, Chatton JY, Martin JL . Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. J Neurosci 2003; 23: 8212–8220.

    Article  CAS  Google Scholar 

  69. Rosburg T, Trautner P, Ludowig E, Schaller C, Kurthen M, Elger CE . Hippocampal event-related potentials to tone duration deviance in a passive oddball paradigm in humans. Neuroimage 2007; 37: 274–281.

    Article  Google Scholar 

  70. Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX . Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 2008; 582: 359–364.

    Article  CAS  Google Scholar 

  71. Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori Y, Gum E et al. Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci 2003; 23: 10681–10690.

    Article  CAS  Google Scholar 

  72. Langan SJ, Deary IJ, Hepburn DA, Frier BM . Cumulative cognitive impairment following recurrent severe hypoglycemia in adult patient with insulin-treated diabetes mellitus. Diabetologia 1991; 34: 337–344.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the children and their families for participating in the study. We also thank anonymous reviewers for their helpful comments. GSK, AW, HR, BMM, and MMN were supported by the Deutsche Forschungsgemeinschaft. GSK, BMM, MMN were funded by the EU in the Sixth Framework Program, LifeScienceHealth, project title Dyslexia genes and neurobiological pathways (Neurodys, 018696). MMN received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung.

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  1. D Roeske and K U Ludwig: These authors contributed equally to this work.

Authors and Affiliations

  1. Max-Planck Institute of Psychiatry, Munich, Germany

    D Roeske & B Müller-Myhsok

  2. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    K U Ludwig, J Becker, F F Brockschmidt, P Hoffmann & M M Nöthen

  3. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Ludwig-Maximilians-University Munich, Munich, Germany

    N Neuhoff, J Bartling, J Bruder & G Schulte-Körne

  4. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany

    A Warnke

  5. Department of Child and Adolescent Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany

    H Remschmidt

  6. Institute of Human Genetics, University of Bonn, Bonn, Germany

    P Hoffmann & M M Nöthen

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Roeske, D., Ludwig, K., Neuhoff, N. et al. First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children. Mol Psychiatry 16, 97–107 (2011). https://doi.org/10.1038/mp.2009.102

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