Abstract
A recent genome-wide association study on dyslexia in 51,800 affected European adults and 1,087,070 controls detected 42 genome-wide significant single nucleotide variants (SNPs). The association between rs2624839 in SEMA3F and reading fluency was replicated in a Chinese cohort. This study explores the genetic overlap between Chinese and English word reading, vocabulary knowledge and spelling, and aims at replicating the association in a unique cohort of bilingual (Chinese–English) Hong Kong Chinese twins. Our result showed an almost complete genetic overlap in vocabulary knowledge (r2 = 0.995), and some genetic overlaps in word reading and spelling (r2 = 0.846, 0.687) across the languages. To investigate the region near rs2624839, we tested proxy SNPs (rs1005678, rs12632110 and rs12494414) at the population level (n = 305–308) and the within-twin level (n = 342–344 [171–172 twin pairs]). All the three SNPs showed significant associations with quantitative Chinese and English vocabulary knowledge (p < 0.05). The strongest association after multiple testing correction was between rs12494414 and English vocabulary knowledge at the within-twin level (p = 0.004). There was a trend of associations with word reading and spelling in English but not in Chinese. Our result suggested that the region near rs2624839 is one of the common genetic factors across English and Chinese vocabulary knowledge and unique factors of English word reading and English spelling in bilingual Chinese twins. A larger sample size is required to validate our findings. Further studies on the relationship between variable expression of SEMA3F, which is important to neurodevelopment, and language and literacy are encouraged.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Abascal F, Acosta R, Addleman NJ, Adrian J, Afzal V, Aken B, Akiyama JA, Jammal OA, Amrhein H, Anderson SM, Andrews GR, Antoshechkin I, Ardlie KG, Armstrong J, Astley M, Banerjee B, Barkal AA, Barnes IHA, Barozzi I, Zimmerman J (2020) Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583(7818):699–710. https://doi.org/10.1038/s41586-020-2493-4
Andreola C, Mascheretti S, Belotti R, Ogliari A, Marino C, Battaglia M, Scaini S (2021) The heritability of reading and reading-related neurocognitive components: a multi-level meta-analysis. Neurosci Biobehav Rev 121:175–200. https://doi.org/10.1016/J.NEUBIOREV.2020.11.016
Boker S, Neale M, Maes H, Wilde M, Spiegel M, Brick T, Spies J, Estabrook R, Kenny S, Bates T, Mehta P, Fox J (2011) OpenMx: an open source extended structural equation modeling framework. Psychometrika 76(2):306–317. https://doi.org/10.1007/s11336-010-9200-6
Chen Q, Kong Y, Gao W, Mo L (2018) Effects of socioeconomic status, parent-child relationship, and learning motivation on reading ability. Front Psychol 9:1297. https://doi.org/10.3389/FPSYG.2018.01297/BIBTEX
Chow BWY, Ho CSH, Wong SWL, Waye MMY, Bishop DVM (2011) Genetic and environmental influences on chinese language and reading abilities. PLoS One 6(2):e16640. https://doi.org/10.1371/JOURNAL.PONE.0016640
Cunningham F, Allen JE, Allen J, Alvarez-Jarreta J, Amode MR, Armean IM, Austine-Orimoloye O, Azov AG, Barnes I, Bennett R, Berry A, Bhai J, Bignell A, Billis K, Boddu S, Brooks L, Charkhchi M, Cummins C, DaRin Fioretto L, Flicek P (2022) Ensembl 2022. Nucleic Acids Res 50(D1):D988–D995. https://doi.org/10.1093/NAR/GKAB1049
Davies G, Lam M, Harris SE, Trampush JW, Luciano M, Hill WD, Hagenaars SP, Ritchie SJ, Marioni RE, Fawns-Ritchie C, Liewald DCM, Okely JA, Ahola-Olli AV, Barnes CLK, Bertram L, Bis JC, Burdick KE, Christoforou A, Derosse P, Deary IJ (2018) Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun 9(1):1–16. https://doi.org/10.1038/s41467-018-04362-x
dbSNP (n.d.). Retrieved June15, 2023, from https://www.ncbi.nlm.nih.gov/snp/
Doust C, Fontanillas P, Eising E, Gordon SD, Wang Z, Alagöz G, Molz B, Aslibekyan S, Auton A, Babalola E, Bell RK, Bielenberg J, Bryc K, Bullis E, Coker D, Partida GC, Dhamija D, Das S, Elson SL, Luciano M (2022) Discovery of 42 genome-wide significant loci associated with dyslexia. Nat Genet. https://doi.org/10.1038/s41588-022-01192-y
Duncan BW, Mohan V, Wade SD, Truong Y, Kampov-Polevoi A, Temple BR, Maness PF (2021) Semaphorin3F drives dendritic spine pruning through Rho-GTPase signaling. Mol Neurobiol 58(8):3817. https://doi.org/10.1007/S12035-021-02373-2
Fishilevich S, Nudel R, Rappaport N, Hadar R, Plaschkes I, Stein TI, Rosen N, Kohn A, Twik M, Safran M, Lancet D, Cohen D (2017) GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database. https://doi.org/10.1093/DATABASE/BAX028
Friedman NP, Banich MT, Keller MC (2021) Twin studies to GWAS: there and back again. Trends Cogn Sci 25(10):855–869. https://doi.org/10.1016/J.TICS.2021.06.007
Hatzikotoulas K, Gilly A, Zeggini E (2014) Using population isolates in genetic association studies. Brief Funct Genom 13(5):371. https://doi.org/10.1093/BFGP/ELU022
Hill WD, Marioni RE, Maghzian O, Ritchie SJ, Hagenaars SP, McIntosh AM, Gale CR, Davies G, Deary IJ (2018) A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence. Mol Psychiatry 24(2):169–181. https://doi.org/10.1038/s41380-017-0001-5
Ho CSH, Chan DWO, Lee SH, Tsang SM, Luan VH (2004) Cognitive profiling and preliminary subtyping in Chinese developmental dyslexia. Cognition 91(1):43–75. https://doi.org/10.1016/S0010-0277(03)00163-X
Ho S, Chan D, Chung K, Tsang S, Lee S, Cheng WYR (2007) Hong Kong test of specific learning difficulties in reading and writing for primary school students, 2nd edn
Howe LJ, Nivard MG, Morris TT, Hansen AF, Rasheed H, Cho Y, Chittoor G, Ahlskog R, Lind PA, Palviainen T, van derZee MD, Cheesman R, Mangino M, Wang Y, Li S, Klaric L, Ratliff SM, Bielak LF, Nygaard M, Davies NM (2022) Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects. Nat Genet. https://doi.org/10.1038/s41588-022-01062-7
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, Kosmicki JA, Arbelaez J, Cui W, Schwartz GB, Chow ED, Kanterakis E, Gao H, Kia A, Batzoglou S, Sanders SJ, Farh KKH (2019) Predicting splicing from primary sequence with deep learning. Cell 176(3):535-548.e24. https://doi.org/10.1016/J.CELL.2018.12.015
Kim Y-SG (2020) Interactive dynamic literacy model: an integrative theoretical framework for reading-writing relations, pp 11–34. https://doi.org/10.1007/978-3-030-38811-9_2
Lind PA, Luciano M, Wright MJ, Montgomery GW, Martin NG, Bates TC (2010) Dyslexia and DCDC2: normal variation in reading and spelling is associated with DCDC2 polymorphisms in an Australian population sample. Eur J Hum Genet 18(6):668–673. https://doi.org/10.1038/ejhg.2009.237
Lo JCM, Ye Y, Tong X, McBride C, Ho CSH, Waye MMY (2018) Delayed copying is uniquely related to dictation in bilingual Cantonese–English-speaking children in Hong Kong. Writ Syst Res 10(1):26–42. https://doi.org/10.1080/17586801.2018.1481902
Luciano M, Evans DM, Hansell NK, Medland SE, Montgomery GW, Martin NG, Wright MJ, Bates TC (2013) A genome-wide association study for reading and language abilities in two population cohorts. Genes Brain Behav 12(6):645–652. https://doi.org/10.1111/gbb.12053
Maughan B, Messer J, Collishaw S, Pickles A, Snowling M, Yule W, Rutter M (2009) Persistence of literacy problems: spelling in adolescence and at mid-life. J Child Psychol Psychiatry 50(8):893–901. https://doi.org/10.1111/J.1469-7610.2009.02079.X
McBride-Chang C, Chung KKH, Tong X (2011) Copying skills in relation to word reading and writing in Chinese children with and without dyslexia. J Exp Child Psychol 110(3):422–433. https://doi.org/10.1016/J.JECP.2011.04.014
Müller B, Wilcke A, Czepezauer I, Ahnert P, Boltze J, Kirsten H, Friederici AD, Emmrich F, Brauer J, Neef N, Skeide M, Schaadt G, Kraft I, Dörr L (2016) Association, characterisation and meta-analysis of SNPs linked to general reading ability in a German dyslexia case-control cohort. Sci Rep. https://doi.org/10.1038/SREP27901
Neale M, Cardon L (1992) Methodology for genetic studies of twins and families. Springer Science & Business Media, New York
Neale M, Eaves L, Bartels M, Boomsma D, Posthuma D, Bates T (2017) The 2018 international workshop on statistical genetic methods for human complex traits. Behav Genet 47:729–730
Paracchini S, Steer CD, Buckingham L-L, Morris AP, Ring S, Scerri T, Stein J, Pembrey ME, Ragoussis J, Golding J, Monaco AP (2008) Association of the KIAA0319 dyslexia susceptibility gene with reading skills in the general population. Am J Psychiatry 165(12):1576–1584. https://doi.org/10.1176/APPI.AJP.2008.07121872
Perfetti C (2010) Decoding, vocabulary, and comprehension. The golden triangle of reading skill. In: McKeown MG, Kucan L (eds) Bringing reading research to life. Guilford Press, New York
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, DeBakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559. https://doi.org/10.1086/519795
Sahay A, Molliver ME, Ginty DD, Kolodkin AL (2003) Semaphorin 3F is critical for development of limbic system circuitry and is required in neurons for selective CNS axon guidance events. J Neurosci 23(17):6671. https://doi.org/10.1523/JNEUROSCI.23-17-06671.2003
Savage JE, Jansen PR, Stringer S, Watanabe K, Bryois J, DeLeeuw CA, Nagel M, Awasthi S, Barr PB, Coleman JRI, Grasby KL, Hammerschlag AR, Kaminski JA, Karlsson R, Krapohl E, Lam M, Nygaard M, Reynolds CA, Trampush JW, Posthuma D (2018) Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence. Nat Genet 50(7):912–919. https://doi.org/10.1038/s41588-018-0152-6
Scerri TS, Morris AP, Buckingham LL, Newbury DF, Miller LL, Monaco AP, Bishop DVM, Paracchini S (2011) DCDC2, KIAA0319 and CMIP are associated with reading-related traits. Biol Psychiatry 70(3):237–245. https://doi.org/10.1016/J.BIOPSYCH.2011.02.005
Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D (2019) Benefits and limitations of genome-wide association studies. Nat Rev Genet 20(8):467–484. https://doi.org/10.1038/s41576-019-0127-1
Tong X, McBride-Chang C (2010) Developmental models of learning to read Chinese words. Dev Psychol 46(6):1662–1676. https://doi.org/10.1037/A0020611
Tong X, Mcbride-Chang C, Shu H, Wong AMY (2009) Morphological awareness, orthographic knowledge, and spelling errors: keys to understanding early Chinese literacy acquisition. Sci Stud Read 13(5):426–452. https://doi.org/10.1080/10888430903162910
Tong X, McBride C, Ho CSH, Waye MMY, Chung KKH, Wong SWL, Chow BWY (2018) Within- and cross-language contributions of morphological awareness to word reading and vocabulary in Chinese–English bilingual learners. Read Writ 31(8):1765–1786. https://doi.org/10.1007/S11145-017-9771-Z/TABLES/5
Tosto MG, Hayiou-Thomas ME, Harlaar N, Prom-Wormley E, Dale PS, Plomin R (2017) The genetic architecture of oral language, reading fluency, and reading comprehension: a twin study from 7 to 16 years. Dev Psychol 53(6):1115. https://doi.org/10.1037/DEV0000297
Venkatesh SK, Siddaiah A, Padakannaya P, Ramachandra NB (2013) Analysis of genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in Indian population. J Hum Genet 58(8):531–538. https://doi.org/10.1038/JHG.2013.46
Wang Q, Chiu SL, Koropouli E, Hong I, Mitchell S, Easwaran TP, Hamilton NR, Gustina AS, Zhu Q, Ginty DD, Huganir RL, Kolodkin AL (2017) Neuropilin-2/PlexinA3 receptors associate with GluA1 and mediate Sema3F-dependent homeostatic scaling in cortical neurons. Neuron 96(5):1084-1098.e7. https://doi.org/10.1016/J.NEURON.2017.10.029
Wang Z, Zhao S, Zhang L, Yang Q, Cheng C, Ding N, Zhu Z, Shu H, Liu C, Zhao J (2023) A genome-wide association study identifies a new variant associated with word reading fluency in Chinese children. Genes Brain Behav 22(1):e12833. https://doi.org/10.1111/GBB.12833
Waye MMY, Poo LK, Ho CS-H (2017) Study of genetic association with DCDC2 and developmental dyslexia in Hong Kong chinese children. Clin Pract Epidemiol Mental Health 13(1):104. https://doi.org/10.2174/1745017901713010104
Wilcke A, Weissfuss J, Kirsten H, Wolfram G, Boltze J, Ahnert P (2009) The role of gene DCDC2 in German dyslexics. Ann Dyslexia 59(1):1–11. https://doi.org/10.1007/S11881-008-0020-7/TABLES/3
Wong SWL, Chow BWY, Ho CSH, Waye MMY, Bishop DVM (2014) Genetic and environmental overlap between Chinese and English reading-related skills in Chinese children. Dev Psychol 50(11):2539. https://doi.org/10.1037/A0037836
Wong PCM, Kang X, So HC, Choy KW (2022) Contributions of common genetic variants to specific languages and to when a language is learned. Sci Rep 12(1):1–13. https://doi.org/10.1038/s41598-021-04163-1
Zhou Z, Tan C, Chau MHK, Jiang X, Ke Z, Chen X, Cao Y, Kwok YK, Bellgard M, Leung TY, Choy KW, Dong Z (2023) TEDD: a database of temporal gene expression patterns during multiple developmental periods in human and model organisms. Nucleic Acids Res 51(D1):D1168–D1178. https://doi.org/10.1093/NAR/GKAC978
Zou L, Zhu K, Jiang Q, Xiao P, Wu X, Zhu B, Song R (2022) Quality of life in Chinese children with developmental dyslexia: a cross-sectional study. BMJ Open 12(1):e052278. https://doi.org/10.1136/BMJOPEN-2021-052278
Acknowledgements
We thank the participants for their participation.
Funding
This study was partially funded by the Research Grants Council of the Hong Kong Special Administration Region (C4054-17WF) and the Theme-based Research Scheme from the Hong Kong Special Administrative Region Research Grants Council (T44-410/21-N).
Author information
Authors and Affiliations
Contributions
CYC and KWC contributed and composed the study design. CYC, DJP, MZ drafted the manuscript, collected the genotype data, and interpreted the data. KWC, SP, H-CS, UM, WJ, and CM interpreted the data. The authors approved the final version of manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Ethics approval
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Chinese University of Hong Kong (CREC Ref. No.: 2021.237).
Consent to participate
Informed consent was obtained from all individual participants and their parents included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Chung, C.Y., Pan, D.J., Paracchini, S. et al. Dyslexia-related loci are significantly associated with language and literacy in Chinese–English bilingual Hong Kong Chinese twins. Hum. Genet. 142, 1519–1529 (2023). https://doi.org/10.1007/s00439-023-02594-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-023-02594-6