分子遗传学的研究极大地推进了我们对阅读障碍的理解，这对于深入了解阅读障碍者大脑结构和功能特征及其认知发展缺陷具有重要的推动意义，也有利于阅读障碍儿童的鉴别与矫治。目前研究者已经发现了多个阅读障碍候选基因，然而阅读障碍是受到多基因共同作用的复杂遗传疾病，其表现形式还受到语言文化环境等多种因素的影响，从不同研究中得到的结果仍然存在较大的差异。目前，对于这些候选基因的作用的实质还没有明确的结论，研究还处于初步积累阶段，仍然需要大量的研究对已有结果进行重复验证。当前正在发展的多中心合作研究将极大地促进阅读障碍候选基因的研究，帮助我们更好地探讨基因作用跨语言、文化、种族的普遍性和特殊性。

另外，目前的研究者普遍认同阅读障碍代表了阅读能力正态分布的末端，他们只存在发展上的落后（e.g.，Ho et al.，2007；Shaywitz & Shaywitz，2005）。既然阅读障碍代表阅读能力的末端，属于阅读能力连续体的一部分，那么阅读障碍的候选基因对一般群体阅读能力的作用如何是值得研究者进一步探讨的问题。此外，研究者主要采用横断研究的方法，仅在单一时间点上探讨候选基因与阅读障碍的关系，而行为研究已经证明，阅读障碍者的认知缺陷及障碍程度在个体发展的不同阶段存在异质性，因此后续研究还需要从纵向追踪的角度进行深入分析。

摘要 Abstract

Developmental dyslexia, DD, is a complex genetic disorder, and with multiple cognitive deficits.Previous molecular genetic studies mainly adopted case-control design to investigate possible candidate genes for DD, and have reported several candidate genes (such as DYX1C1，DCDC2，KIAA0319/TTRAP).Further investigation revealed that these candidate genes were also in contribution to reading-related cognitive skills.This paper introduces previous studies on candidate genes of DD, including findings of genetic association studies on Chinese population.

Keywords

developmental dyslexia, candidate gene, association analysis, cognitive phenotype

参考文献 Reference

张玉平.（2012）.阅读障碍的候选基因：来自汉语儿童的证据.北京：北京师范大学.

Anthoni, H., Zucchelli, M., Matsson, H., Muller-Myhsok, B., Fransson, I., Schumacher, J., ...Griesemann, H.(2007).A locus on 2p12 containing the co-regulated MRPL19 and C2ORF3 genes is associated to dyslexia.Human Molecular Genetics, 16(6): 667-677.

Bates, T.C., Lind, P.A., Luciano, M., Montgomery, G.W., Martin, N.G., & Wright, M.J.(2009).Dyslexia and DYX1C1: Deficits in reading and spelling associated with a missense mutation.Molecular Psychiatry, 15: 1190-1196.

Bellini, G., Bravaccio, C., Calamoneri, F., Cocuzza, M.D., Fiorillo, P., Gagliano, A., ...Militerni, R.(2005).No evidence for association between dyslexia and DYX1C1 functional variants in a group of children and adolescents from Southern Italy.Journal of Molecular Neuroscience, 27(3): 311-314.

Cope, N., Harold, D., Hill, G., Moskvina, V., stevenson, J., Holmans, P., ...Williams, J.(2005).Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia.American Joural of Human Gentics., 76(4): 581-591.

Couto, J.M., Livne‐Bar, I., Huang, K., Xu, Z., Cate-Carter, T., Feng, Y., ...Kerr, E.N.(2010).Association of reading disabilities with regions marked by acetylated H3 histones in KIAA0319. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 153(2): 447-462.

Davis, C.J., Gayán, J., Knopik, V.S., Smith, S.D., Cardon, L.R., Pennington, B.F., ...DeFries, J.C.(2001).Etiology of reading difficulties and rapid naming: The Colorado twin study of reading disability.Behavior Genetics, 31(6): 625-635.

Deffenbacher, K.E., Kenyon, J.B., Hoover, D.M., Olson, R.K., Pennington, B.F., DeFries, J.C., & Smith, S.D.(2004).Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: Linkage and association analyses.Hum Genet, 115(2): 128-138.

Elbert, A., Lovett, M.W., Cate-Carter, T., Pitch, A., Kerr, E.N., & Barr, C.L.(2011).Genetic variation in the KIAA0319 5’ region as a possible contributor to dyslexia.Behavior Genetics, 41(1): 77-89.

Finucci, J.M., Guthrie, J.T., Childs, A.L., Abbey, H., & Childs, B.(1976).The genetics of specific reading disability.Annals of Human Genetics, 40(1): 1-23.

Fisher, S.E., & DeFries, J.C.(2002).Developmental dyslexia: Genetic dissection of a complex cognitive trait.Nature Reviews Neuroscience, 3(10): 767-780.

Fisher, S.E., & Francks, C.(2006).Genes, cognition and dyslexia: Learning to read the genome.Trends in Cognitive Sciences, 10(6): 250-257.

Francks, C., MacPhie, I.L., & Monaco, A.P.(2002).The genetic basis of dyslexia.Lancet Neurol, 1(8): 483-490.

Francks, C., Paracchini, S, Smith, S.D., Richardson, A.J., Scerri, T.S., Cardon, L.R., ...Monaco, A.P.(2004).A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States.Am.J.Hum.Genet., 75: 1046-1058.

Gilger, J.W., Pennington, B.F., Harbeck, R.J., DeFries, J.C., Kotzin, B., Green, P., & Smith, S.(1998).A twin and family study of the association between immune system dysfunction and dyslexia using blood serum immunoassay and survey data.Brain and cognition, 36(3): 310-333.

Hannula-Jouppi, K., Kaminen-Ahola, N., Taipale, M., Eklund, R., Nopola-Hemmi, J., K??ri?inen, H., & Kere, J.(2005).The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.PLoS Genet, 1(4): 467-474.

Harold, D., Paracchini, S., Scerri, T., Dennis, M., Cope, N., Hill, G., ...Owen, M.J.(2006).Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia.Molecular Psychiatry, 11: 1085-1091.

Ho, C.S.H., Chan, D.W., Chung, K.K.H., Lee, S.H., & Tsang, S.M.(2007).In search of subtypes of Chinese developmental dyslexia.Journal of Experimental Child Psychology, 97(1): 61-83.

Hoggart, C.J., Parra, E.J., Shriver, M.D., Bonilla, C., Kittles, R.A., Clayton, D.G., & McKeigue, P.M.(2003).Control of confounding of genetic associations in stratified populations.American Journal of Human Genetics, 72(6): 1492-1504.

Kaminen-Ahola, N.(2007).Susceptibility genes and neurodevelopmental mechanisms in dyslexia.Helsinki:University of Helsinki.

Kere, J.(2011).Molecular genetics and molecular biology of dyslexia.Wiley Interdisciplinary Reviews: Cognitive Science, 2(4): 441-448.

Landerl K., Wimmer, H., & Moser, E.(1997).Salzburger Lese- und Rechtschreibtest(SLT) [Salzburg Reading and Spelling Test (SLT)].Bern:Huber.

Leventer, R.J.(2005).Topical review: Genotype-phenotype correlation in lissencephaly and subcortical band heterotopia: The key questions answered.Journal of Child Neurology, 20(4): 307-312.

Lim, C.K.P., Ho, C.S.H., Chou, C.H.N., & Waye, M.M.Y.(2011).Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children.Behavioral and Brain Functions, 7(1): 16.

Lim C.K, Wong, A.M., Ho, C.S., & Waye, M.M.(2014).A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children.Behavioral and Brain Functions, 10(23).

Lind, P.A., Luciano, M., Wright, M.J., Montgomery, G.W., Martin, N.G., & Bates, T.C.(2010).Dyslexia and DCDC2: Normal variation in reading and spelling is associated with DCDC2 polymorphisms in an Australian population sample.European Journal of Human Genetics, 18(6): 668-673.

Luciano, M., Lind, P.A., Duffy, D.L., Castles, A., Wright, M.J., Montgomery, G.W., ...Bates, T.C.(2007).A haplotype spanning KIAA0319 and TTRAP is associated with normal variation in reading and spelling ability.Biological Psychiatry, 62(7): 811-817.

Ludwig, K.U., Roeske, D., Schumacher, J., Schulte-K?rne, G., K?nig, I.R., Warnke, A., ...Müller-Myhsok, B.(2008).Investigation of interaction between DCDC2 and KIAA0319 in a large German dyslexia sample.J Neural Transm,115(11):1587-1589.

Lyytinen, H., Leinonen, S., Nikula, M., et al.(1995).In search of the core features of dyslexia: Observations concerning dyslexia in the highly orthographically regular Finnish language.In: Virginia Wise Berninger (Ed.), The varieties of orthographic knowledge II: Relationships to phonology, reading, and writing.Berlin:Springer Netherlands, 177-204.

Marino, C., Giorda, R., Lorusso, M.L., Vanzin, L., Salandi, N., Nobile, M., ...Battaglia, M.(2005).A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia.European Journal of Human Genetics, 13:491-499.

Marino, C., Mascheretti, S., Riva, V., Cattaneo, F., Rigoletto, C., Rusconi, M., ...Molteni, M.(2011).Pleiotropic effects of DCDC2 and DYX1C1 genes on language and mathematics traits in nuclear families of developmental dyslexia.Behavior Genetics,41(1):1-10.

Massinen, S., Tammimies, K., Tapia-Páez, I., Matsson, H., Hokkanen, M.E., S?derberg, O., ...Treuter, E.(2009).Functional interaction of DYX1C1 with estrogen receptors suggests involvement of hormonal pathways in dyslexia.Human Molecular Genetics, 18(15): 2802.

Meng, H, Smith, Shelley D, Hager, Karl, Held, Matthew, Liu, Jonathan, Olson, Richard K, ...O’Reilly-Pol, Thomas.(2005).DCDC2 is associated with reading disability and modulates neuronal development in the brain.Proceedings of the National Academy of Sciences of the United States of America, 102(47): 17053-17058.

Newbury, D.F., Paracchini, S., Scerri, T.S., Winchester, L., Addis, L., Richardson, A.J., ...Monaco, A.P.(2010).Investigation of dyslexia and SLI risk variants in reading-and language-impaired subjects.Behavior Genetics, 41(1): 90-104.

Nopola-Hemmi, J., Taipale, M., Haltia, T., Lehesjoki, A.E., Voutilainen, A., & Kere, J.(2000).Two translocations of chromosome 15q associated with dyslexia.Journal of Medical Genetics,37:771-775.

Olsen, J., Christensen, K., Murray, J., & Ekbom, A.(2010).Sources of error in genetic epidemiology.In: Olsen, J., Christensen, K., Murray, J., & Ekbom, A.(Eds.), An introduction to epidemiology for health professionals.New York: Springer, 135-137.

Olson, R.K.(2002).Dyslexia: Nature and nurture.Dyslexia, 8(3): 143-159.

Olson, R.K., Forsberg , H., & Wise, B.(1994).Genes, environment, and the development of orthographic skills.In: V.W.Berninger (Ed.), The varieties of orthographic knowledge I: Theoretical developmental issues.Netherlands: Springer, 27-71.

Paracchini, S., Ang, Q.W., Stanley, F.J., Monaco, A.P., Pennell, C.E., & Whitehouse, A.J.O.(2010).Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population.Genes, Brain and Behavior, 10(2): 158-165.

Paracchini, S., Thomas, A., Castro, S., Lai, C., Paramasivam, M., Wang, Y., ...Monaco, A.P.(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): 1659-1666.

Paracchini, Silvia, Steer, Colin, Buckingham, Lyn-Louise, Morris, Andrew, Ring, Susan, Scerri, Thomas, ...Golding, Jean.(2008).Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population.American Journal of Psychiatry, 165(12): 1576-1584.

Poelmans, G., Buitelaar, J.K., Pauls, D.L., & Franke, B.(2011).A theoretical molecular network for dyslexia: Integrating available genetic findings.Molecular psychiatry, 16(4): 365-382.

Pype, S., Declercq, W., Ibrahimi, A., Michiels, C., van Rietschoten, J.G.I., Dewulf, N., ...Remacle, J.E.(2000).TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors(TRAFs), and that inhibits nuclear factor-κB activation.Journal of Biological Chemistry, 275(24): 18586-18593.

Rosen, G.D., Bai, J., Wang, Y., Fiondella, C.G., Threlkeld, S.W., LoTurco, J.J., & Galaburda, A.M.(2007).Disruption of neuronal migration by RNAi of DYX1C1 results in neocortical and hippocampal malformations.Cerebral Cortex, 17(11):2562-2572.

Scerri, T.S., Fisher, S.E., Francks, C., MacPhie, I.L., Paracchini, S., Richardson, A.J., ...Monaco, A.P.(2004).Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK.Journal of Medical Genetics, 41(11): 853-857.

Scerri, T.S., & Schulte-K?rne, G.(2010).Genetics of developmental dyslexia.European Child & Adolescent Psychiatry, 19(3): 179-197.

Scerri, T.S., Morris, A.P., Buckingham, L.L., Newbury, D.F., Miller, L.L., Monaco, A.P., ...Paracchini, S.(2011).DCDC2, KIAA0319 and CMIP are associated with reading-related traits.Biological Psychiatry, 70(3): 237-245.

Schumacher, J., Anthoni, H., Dahdouh, F., K?nig, I.R., Hillmer, A.M., Kluck, N., ...Remschmidt, H.(2006).Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia.American Journal of Human Genetics, 78(1): 52-62.

Shapiro, B.K.(2001).Specific reading disability: A multiplanar view.Mental Retardation and Developmental Disabilities Research Reviews, 7(1): 13-20.

Shaywitz, S.E., & Shaywitz, B.A.(2005).Dyslexia (specific reading disability).Biological psychiatry, 57(11): 1301-1309.

Shu, H., McBride-Chang, C., Wu, S., & Liu, H.(2006).Understanding Chinese developmental dyslexia: Morphological awareness as a core cognitive construct.Journal of Educational Psychology, 98(1): 122-133.

Shu, H., Meng, X., Chen, X., Luan, H., & Cao, F.(2005).The subtypes of developmental dyslexia in Chinese: Evidence from three cases.Dyslexia, 11(4): 311-329.

Snowling, M.J., Gallagher, A., & Frith, U.(2003).Family risk of dyslexia is continuous: Individual differences in the precursors of reading skill.Child Development, 74(2): 358-373.

Su, M., Wang, J., Maurer, U., Zhang, Y., Li, J., McBride, C., ...Shu, H.(2015).Geneenvironment interaction on neural mechanisms of orthographic processing in Chinese children.Journal of Neurolinguistics, 33: 172-186.

Sun, Y., Gao, Y., Zhou, Y., Chen, H., Wang, G., Xu, J., ...Tan, L.(2014).Association study of developmental dyslexia candidate genes DCDC2 and KIAA0319 in Chinese population.American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 165(8): 627-634.

Taipale, M., Kaminen, N., Nopola-Hemmi, J., Haltia, T., Myllyluoma, B., Lyytinen, H., ...Hannula-Jouppi, K.(2003).A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain.Proceedings of the National Academy of Sciences of the United States of America, 100(20): 11553-11558.

Velayos-Baeza, A., Toma, C., da Roza, S., Paracchini, S., & Monaco, A.P.(2007).Alternative splicing in the dyslexia-associated gene KIAA0319.Mammalian Genome, 18(9): 627-634.

Velayos-Baeza, A., Toma, C., Paracchini, S., & Monaco, A.P.(2008).The dyslexiaassociated gene KIAA0319 encodes highly N- and O-glycosylated plasma membrane and secreted isoforms.Human Molecular Genetics, 17(6): 859-871.

Vellutino, F.R., Fletcher, J.M., Snowling, M.J., & Scanlon, D.M.(2004).Specific reading disability (dyslexia): What have we learned in the past four decades? Journal of child psychology and psychiatry, 45(1): 2-40.

Wigg, K.G., Couto, J.M., Feng, Y., Anderson, B., Cate-Carter, T.D., Macciardi, F., ...Barr, C.L.(2004).Support for EKN1 as the susceptibility locus for dyslexia on 15q21.Molecular Psychiatry, 9: 1111-1121.

Wilcke, A., Weissfuss, J., Kirsten, H., Wolfram, G., Boltze, J., & Ahnert, P.(2009).The role of gene DCDC2 in German dyslexics.Annals of dyslexia, 59(1): 1-11.

Williams, J., & O’Donovan, M.C.(2006).The genetics of developmental dyslexia.Eur J Hum Genet, 14(6): 681-689.

Zhang, Y., Li, J., Tardif, T., Burmeister, M., Villafuerte, S.M., McBride-Chang, C., ...Zhang, Z.(2012).Association of the DYX1C1 dyslexia susceptibility gene with orthography in the Chinese population.PloS one, 7(9): e42969.

Ziegler, J.C., Bertrand, D., Tóth, D., Csépe, V., Reis, A., Faísca, L., ...Blomert, L.(2010).Orthographic depth and its impact on universal predictors of reading.Psychological Science, 21(4): 551-559.

[1] 成都医学院心理学系

[2] 北京师范大学认知神经科学与学习国家重点实验室