Genetic research into dyslexia

Main articles: dyslexia and dyslexia research

The genetic research into dyslexia has its roots in the work of Galaburda and Kemper, 1979,[1] and Galaburda et al. 1985,[2] from the examination of post-autopsy brains of people with dyslexia. When they observed anatomical differences in the language center in a dyslexic brain, they showed microscopic cortical malformations known as ectopias and more rarely vascular micro-malformations, and in some instances these cortical malformations appeared as a microgyrus. These studies and those of Cohen et al. 1989[3] suggested abnormal cortical development which was presumed to occur before or during the sixth month of foetal brain development.[4]

Overview

High genetic concordance found in twin studies suggest a significant genetic influence on reading ability,[5][6] although the degree depends on the definition of dyslexia.[7] Linkage analysis and genetic association studies (typically quantitative trait locus association studies, which use microarrays to look at single nucleotide polymorphisms of multiple genes at once) have been used to identify candidate genes that may be implicated in dyslexia.[8] Several genes have been linked to dyslexia, including DCDC2[9][10] and KIAA0319[9][11] on chromosome 6,[12][13] DYX1C1 on chromosome 15,[9][12] ROBO1,[14] DYX3,[15] the language-disorder candidate gene CMIP,[16] and several others. However, these genes account for a small proportion of variance in reading disability, often less than 0.5%.[17][18] Additionally, the findings are not always replicated. Therefore, no single gene is definitively implicated in dyslexia. A 2007 review reported that no specific cognitive processes are known to be influenced by the proposed genes.[19]

It is likely that multiple genes, as well as the environment, interact to influence reading ability. The Generalist Genes Hypothesis proposes that many of the same genes are implicated within different aspects of a learning disability as well as between different learning disabilities. Indeed, there also appear to be a large genetic influence on other learning abilities, such as language skills.[20] The Generalist Genes Hypothesis supports the findings that many learning disabilities are comorbid, such as speech sound disorder, language impairment, and reading disability,[21] although this is also influenced by diagnostic overlap.

Many of the genes implicated in dyslexia play a role in general neural development. For example, dyslexia candidate genes DYX1C1, ROBO1 KIAA0319, and DCDC2 appear to be involved in neuronal migration.[10][22][23][24] Animal models are especially useful in determining the function of these genes. For example, Gene knockdown in utero of DYX1C1 disrupts hippocampal development and causes impairments in auditory processing and spatial learning in rodents[25] and mutations in DCDC2 impairs visuo-spatial memory, visual discrimination, and long-term memory in mice.[26] The role of neuronal migration in dyslexia is reviewed in Galaburda (2005).[27]

Genes and chromosomes associated with dyslexia

Molecular studies have linked several forms of dyslexia to genetic markers.[28] Several candidate genes have been identified, including at the two regions first related to dyslexia: ROBO1[29] on chromosome 3, DCDC2[10][29] and KIAA0319,[11][29] on chromosome 6,[30] DYX1C1[29] on chromosome 15 and PCDH11X[31] on chromosome X.

A 2007 review reported that no specific cognitive processes are known to be influenced by the proposed susceptibility genes. Some studies have already started to include neurophysiological (e.g., event-related potential) and imaging (e.g., functional MRI) procedures in their phenotype characterisation of patients. Such samples are an important prerequisite for the identification of those processes that are most proximal to the effects of particular genes and their associated biological pathways.[32]

References

  1. ↑ Galaburda AM, Kemper TL (August 1979). "Cytoarchitectonic abnormalities in developmental dyslexia: a case study". Annals of Neurology. 6 (2): 94–100. doi:10.1002/ana.410060203. PMID 496415.
  2. ↑ Galaburda AM, Sherman GF, Rosen GD, Aboitiz F, Geschwind N (August 1985). "Developmental dyslexia: four consecutive patients with cortical anomalies". Annals of Neurology. 18 (2): 222–33. doi:10.1002/ana.410180210. PMID 4037763.
  3. ↑ Cohen M, Campbell R, Yaghmai F (June 1989). "Neuropathological abnormalities in developmental dysphasia". Annals of Neurology. 25 (6): 567–70. doi:10.1002/ana.410250607. PMID 2472772.
  4. ↑ Habib M (December 2000). "The neurological basis of developmental dyslexia: an overview and working hypothesis". Brain. 123 (Pt 12): 2373–99. doi:10.1093/brain/123.12.2373. PMID 11099442.
  5. ↑ Wadsworth, SJ; DeFries JC; Olson RK; Willcutt EG. (December 2007). "Colorado longitudinal twin study of reading disability". Annals of Dyslexia. 57 (2): 139–60. doi:10.1007/s11881-007-0009-7. PMID 18060583.
  6. ↑ Harlaar, N; Spinath FM; Dale PS; Plomin R (April 2005). "Genetic influences on early word recognition abilities and disabilities: a study of 7-year-old twin". J Child Psychol Psychiatry. 46 (4): 373–84. doi:10.1111/j.1469-7610.2004.00358.x. PMID 15819646.
  7. ↑ Olson, RK (2002). "Dyslexia: nature and nurture". Dyslexia. 8 (3): 143–159. doi:10.1002/dys.228. PMID 12222731.
  8. ↑ Grigorenko EL, Wood FB, Meyer MS (January 1997). "Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15". American Journal of Human Genetics. 60 (1): 27–39. PMC 1712535Freely accessible. PMID 8981944.
  9. 1 2 3 Shastry BS (2007). "Developmental dyslexia: an update". J. Hum. Genet. 52 (2): 104–9. doi:10.1007/s10038-006-0088-z. PMID 17111266.
  10. 1 2 3 Meng H, Smith SD, Hager K (November 2005). "DCDC2 is associated with reading disability and modulates neuronal development in the brain". Proc. Natl. Acad. Sci. U.S.A. 102 (47): 17053–8. Bibcode:2005PNAS..10217053M. doi:10.1073/pnas.0508591102. PMC 1278934Freely accessible. PMID 16278297.
  11. 1 2 Paracchini S, Steer CD, Buckingham LL (December 2008). "Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population". The American Journal of Psychiatry. 165 (12): 1576–84. doi:10.1176/appi.ajp.2008.07121872. PMID 18829873.
  12. 1 2 Bishop, DVM (March 2009). "Genes, cognition, and communication: insights from neurodevelopmental disorders". Annals of the New York Academy of Sciences. 1156 (1): 1–18. Bibcode:2009NYASA1156....1B. doi:10.1111/j.1749-6632.2009.04419.x. PMC 2805335Freely accessible. PMID 19338500.
  13. ↑ Grigorenko EL, Wood FB, Meyer MS, Pauls DL (February 2000). "Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation". American Journal of Human Genetics. 66 (2): 715–23. doi:10.1086/302755. PMC 1288124Freely accessible. PMID 10677331.
  14. ↑ Hannula-Jouppi, Katariina; Nina Kaminen-Ahola; Mikko Taipale; Ranja Eklund; Jaana Nopola-Hemmi; Helena Kääriäinen; Juha Kere (October 2005). "The Axon Guidance Receptor Gene ROBO1 Is a Candidate Gene for Developmental Dyslexia". The Axon Guidance Receptor Gene ROBO1 is a Candidate Gene for Developmental Dyslexia. 1 (4): 0467–0474. doi:10.1371/journal.pgen.0010050. PMC 1270007Freely accessible. PMID 16254601.
  15. ↑ Fagerheim, T; Raeymaekers P; Tønnessen FE; Pedersen M; Tranebjaerg L; Lubs HA. (September 1999). "A new gene (DYX3) for dyslexia is located on chromosome 2". J Med Genet. 36 (9): 664–9. doi:10.1136/jmg.36.9.664 (inactive 2016-10-12). PMC 1734428Freely accessible. PMID 10507721.
  16. ↑ Scerri, TS; Morris AP; Buckingham LL; Newbury DF; Miller LL; Monaco AP; Bishop DV; Paracchini S. (August 2011). "DCDC2, KIAA0319 and CMIP are associated with reading-related traits". DCDC2, KIAA0319 and CMIP are associated with reading-related traits. 70 (3): 237–45. doi:10.1016/j.biopsych.2011.02.005. PMC 3139836Freely accessible. PMID 21457949.
  17. ↑ Butcher, LM; O S P Davis; I W Craig; R Plomin (June 2008). "Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays". Genes Brain Behav. 7 (4): 435–46. doi:10.1111/j.1601-183X.2007.00368.x. PMID 18067574.
  18. ↑ Meaburn, EL; N Harlaar; I W Craig; L C Schalkwyk; R Plomin (2008). "Quantitative trait locus association scan of early reading disability and ability using pooled DNA and 100K SNP microarrays in a sample of 5760 children". Molecular Psychiatry. 13 (7): 729–740. doi:10.1038/sj.mp.4002063. PMID 17684495.
  19. ↑ Schumacher J, Hoffmann P, Schmäl C, Schulte-Körne G, Nöthen MM (May 2007). "Genetics of dyslexia: the evolving landscape". Journal of Medical Genetics. 44 (5): 289–97. doi:10.1136/jmg.2006.046516. PMC 2597981Freely accessible. PMID 17307837.
  20. ↑ Stromswold, Karin (December 2001). "The Heritability of Language: A Review and Metaanalysis of Twin, Adoption, and Linkage Studies.". Language. 77 (4): 647–723. doi:10.1353/lan.2001.0247.
  21. ↑ Pennington BF, Bishop DVM (2009). "Relations Among Speech, Language, and Reading Disorders". Annual Review of Psychology. 60: 283–306. doi:10.1146/annurev.psych.60.110707.163548. PMID 18652545.,
  22. ↑ Kid, T; Brose K; Mitchell KJ; Fetter RD; Tessier-Lavigne M (1998). "Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors". Cell. 92 (2): 205–215. doi:10.1016/S0092-8674(00)80915-0. PMID 9458045.
  23. ↑ Wang, Y; Paramasivam M; Thomas A; Bai J; Kaminen-Ahola N; Kere J; Voskuil J; Rosen GD; Galaburda AM; Loturco JJ. (2006). "DYX1C1 functions in neuronal migration in developing neocortex". Neuroscience. 123 (2): 515–22. doi:10.1016/j.neuroscience.2006.08.022. PMID 16989952.
  24. ↑ Paracchini S, Thomas A, Castro S, Lai C, Paramasivam M, Wang Y, Keating BJ, Taylor JM, Hacking DF, Scerri T, Francks C, Richardson AJ, Wade-Martins R, Stein JF, Knight JC, Copp AJ, Loturco J, Monaco AP (2006). "The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration". Hum. Mol. Genet. 15 (10): 1659–66. doi:10.1093/hmg/ddl089. PMID 16600991.
  25. ↑ Threlkeld, SW; McClure MM; Bai J; Wang Y; LoTurco JJ; Rosen GD; Fitch RH. (March 2007). "Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1". Brain Res Bull. 71 (5): 508–14. doi:10.1016/j.brainresbull.2006.11.005. PMC 1893003Freely accessible. PMID 17259020.
  26. ↑ Gabel, LA; Marin I; LoTurco JJ; Che A; Murphy C; Manglani M; Kass S (November 2011). "Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice". Genes Brain Behav. 10 (8): 868–75. doi:10.1111/j.1601-183X.2011.00727.x. PMC 3212622Freely accessible. PMID 21883923.
  27. ↑ Galaburda, Albert (2005). "Dyslexia—A molecular disorder of neuronal migration". Annals of Dyslexia. 55 (2): 151–165. doi:10.1007/s11881-005-0009-4. PMID 17849191.
  28. ↑ Grigorenko EL, Wood FB, Meyer MS, et al. (January 1997). "Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15". American Journal of Human Genetics. 60 (1): 27–39. PMC 1712535Freely accessible. PMID 8981944.
  29. 1 2 3 4 Paracchini S, Scerri T, Monaco AP (2007). "The genetic lexicon of dyslexia". Annu Rev Genomics Hum Genet. 8: 57–79. doi:10.1146/annurev.genom.8.080706.092312. PMID 17444811.
  30. ↑ Grigorenko EL, Wood FB, Meyer MS, Pauls DL (February 2000). "Chromosome 6p influences on different dyslexia-related cognitive processes: further confirmation". American Journal of Human Genetics. 66 (2): 715–23. doi:10.1086/302755. PMC 1288124Freely accessible. PMID 10677331.
  31. ↑ Veerappa, Avinash; Saldanha M; Padakannaya P; Ramachandra NB (2013). "Genome-wide copy number scan identifies disruption of PCDH11X in developmental dyslexia". American Journal of Medical Genetics Part B. 162: 889–897. doi:10.1002/ajmg.b.32199.
  32. ↑ Schumacher J, Hoffmann P, Schmäl C, Schulte-Körne G, Nöthen MM (May 2007). "Genetics of dyslexia: the evolving landscape". Journal of Medical Genetics. 44 (5): 289–97. doi:10.1136/jmg.2006.046516. PMC 2597981Freely accessible. PMID 17307837.


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