Clinical Practice & Epidemiology in Mental Health




ISSN: 1745-0179 ― Volume 15, 2019
RESEARCH ARTICLE

Study of Genetic Association With DCDC2 and Developmental Dyslexia in Hong Kong Chinese Children



Mary M.Y. Waye1, *, Lim K. Poo2, Connie S-H Ho3
1 The Nethersole School of Nursing, The Nethersole School of Nursing, The Chinese University of Hong Kong, Hong Kong
2 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
3 Department of Psychology, The University of Hong Kong, Hong Kong

Abstract

Background:

Doublecortin domain-containing 2 (DCDC2) is a doublecortin domain-containing gene family member and the doublecortin domain has been demonstrated to bind to tubulin and enhance microtubule polymerization. It has been associated with developmental dyslexia and this protein family member is thought to function in neuronal migration where it may affect the signaling of primary cilia.

Objectives:

The objective of the study is to find out if there is any association of genetic variants of DCDC2 with developmental dyslexia in Chinese children from Hong Kong.

Methods:

The dyslexic children were diagnosed as developmental dyslexia (DD) using the Hong Kong Test of Specific Learning Difficulties in Reading and Writing (HKT-SpLD) by the Department of Health, Hong Kong. Saliva specimens were collected and their genotypes of DCDC2 were studied by DNA sequencing or TaqMan Real Time PCR Assays.

Results:

The most significant marker is rs6940827 which is associated with DD with nominal p-value (0.011). However, this marker did not remain significant after multiple testing corrections and the adjusted p-value from permutation test was 0.1329. Using sliding window haplotype analysis, several haplotypes were found to be nominally associated with DD. The smallest nominal p values was 0.0036 (rs2996452-rs1318700, C-A). However, none of the p values could withstand the multiple testing corrections.

Conclusion:

Despite early findings that DCDC2 is a strong candidate for developmental dyslexia and that some of the genetic variants have been linked to brain structure and functions, our findings showed that DCDC2 is not strongly associated with dyslexia.

Keywords: DCDC2, Developmental dyslexia, Genetic association, Sliding window haplotype analysis, Genetic variants, Chinese.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 13
First Page: 104
Last Page: 114
Publisher Id: CPEMH-13-104
DOI: 10.2174/1745017901713010104

Article History:

Received Date: 10/4/2017
Revision Received Date: 21/6/2017
Acceptance Date: 25/07/2017
Electronic publication date: 21/08/2017
Collection year: 2017

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© 2017 Waye et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department Rm 726, 7th floor, Esther Lee Bldg, The Nethersole School of Nursing, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong, Tel: (852) 39439302; Email: mary-waye@cuhk.edu.hk




1. INTRODUCTION

The first dyslexia candidate gene DYX1C1 was reported [1Taipale M, Kaminen N, Nopola-Hemmi J, et al. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci USA 2003; 100(20): 11553-8.
[http://dx.doi.org/10.1073/pnas.1833911100] [PMID: 12954984]
] and confirmed by various groups [2Grigorenko EL. Developmental dyslexia: an update on genes, brains, and environments. J Child Psychol Psychiatry 2001; 42(1): 91-125.
[http://dx.doi.org/10.1111/1469-7610.00704] [PMID: 11205626]
], including our group [3Lim CK, Ho CS, Chou CH, Waye MM. Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children. Behav Brain Funct 2011; 7: 16.
[http://dx.doi.org/10.1186/1744-9081-7-16] [PMID: 21599957]
], and it has been shown to play a molecular role in brain development. Knocking down the function of DYX1C1 using small interfering RNA (siRNA) resulted in disruption of normal neuronal migration in the developing neocortex of embryonic rat, which could be reversed by the concurrent overexpression of DYX1C1 [4Currier TA, Etchegaray MA, Haight JL, Galaburda AM, Rosen GD. The effects of embryonic knockdown of the candidate dyslexia susceptibility gene homologue Dyx1c1 on the distribution of GABAergic neurons in the cerebral cortex. Neuroscience 2011; 172: 535-46.
[http://dx.doi.org/10.1016/j.neuroscience.2010.11.002] [PMID: 21070838]
-6Szalkowski CE, Fiondella CG, Galaburda AM, Rosen GD, Loturco JJ, Fitch RH. Neocortical disruption and behavioral impairments in rats following in utero RNAi of candidate dyslexia risk gene Kiaa0319. Int J Dev Neurosci 2012; 30(4): 293-302.
[http://dx.doi.org/10.1016/j.ijdevneu.2012.01.009] [PMID: 22326444]
]. Disruption of DYX1C1 also impaired auditory processing and spatial learning in rodent models [7Threlkeld SW, McClure MM, Bai J, et al. Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1. Brain Res Bull 2007; 71(5): 508-14.
[http://dx.doi.org/10.1016/j.brainresbull.2006.11.005] [PMID: 17259020]
].

Various linkage analyses results showed strong evidences for 6p21.3 in relation to dyslexia [8Deffenbacher KE, Kenyon JB, Hoover DM, et al. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: Linkage and association analyses. Hum Genet 2004; 115(2): 128-38.
[http://dx.doi.org/10.1007/s00439-004-1126-6] [PMID: 15138886]
-13Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC. Quantitative trait locus for reading disability on chromosome 6. Science 1994; 266(5183): 276-9.
[http://dx.doi.org/10.1126/science.7939663] [PMID: 7939663]
], though some groups reported some difficulties in confirming their results [14Petryshen TL, Kaplan BJ, Liu MF, Field LL. Absence of significant linkage between phonological coding dyslexia and chromosome 6p23-21.3, as determined by use of quantitative-trait methods: Confirmation of qualitative analyses. Am J Hum Genet 2000; 66(2): 708-14.
[http://dx.doi.org/10.1086/302764] [PMID: 10677330]
] or different results depending on whether the subjects were from UK or USA [15Fisher SE, Francks C, Marlow AJ, et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet 2002; 30(1): 86-91.
[http://dx.doi.org/10.1038/ng792] [PMID: 11743577]
-18Ludwig KU, Roeske D, Schumacher J, et al. Investigation of interaction between DCDC2 and KIAA0319 in a large German dyslexia sample. J Neural Transm (Vienna) 2008; 115(11): 1587-9.
[http://dx.doi.org/10.1007/s00702-008-0124-6] [PMID: 18810304]
]. Deffenbacher et al. (2004) [8Deffenbacher KE, Kenyon JB, Hoover DM, et al. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: Linkage and association analyses. Hum Genet 2004; 115(2): 128-38.
[http://dx.doi.org/10.1007/s00439-004-1126-6] [PMID: 15138886]
] used a similar approach by using single nucleotide polymorphism (SNP) markers in the association study. In the first stage, they refined the region to about 3.24Mb by linkage analysis. After that, high dense SNP markers (~21kp apart) across the highly significant region were used. Thirteen SNPs showed significant association with at least one of the phenotypes. The region of these SNPs clustering contains five genes: VMP, DCDC2, KIAA0319, TTRAP and THEM2.

Thirteen of the seventeen significant associated SNPs were located within KIAA0319. Association of KIAA0319 was further confirmed by a study of two large independent UK samples (Oxford and Cardiff) [19Harold D, Paracchini S, Scerri T, et al. Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Mol Psychiatry 2006; 11(12): 1085-1091, 1061.
[http://dx.doi.org/10.1038/sj.mp.4001904] [PMID: 17033633]
]. Harold et al. (2006) [19Harold D, Paracchini S, Scerri T, et al. Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Mol Psychiatry 2006; 11(12): 1085-1091, 1061.
[http://dx.doi.org/10.1038/sj.mp.4001904] [PMID: 17033633]
] refined the region by 36 SNPs markers and the region flanking from the first intron to 5’ upstream showed the most significant association with developmental dyslexia (DD). rs3212236 located at 5’ was the most significant marker associated with word choice test (OC-choice), orthographic coding using irregular words (OC-irreg), single-word reading ability (READ) and spelling ability (SPELL) in the Oxford sample. Our group has also confirmed that a common haplotype of KIAA0319 contributes to phonological awareness skill in Chinese children [20Lim CK, Wong AM, Ho CS, Waye MM. A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children. Behav Brain Funct 2014; 10: 23.
[http://dx.doi.org/10.1186/1744-9081-10-23] [PMID: 25015435]
]. Recently it has also been reported that brainstem responses as characterized by a reduction in neural discrimination abilities are associated with a higher number of risk alleles of KIAA0319 while no significant association has been found with DCDC2 (rs807724, rs1087266, rs807701, rs793842, rs1091047, rs6922023) and performance in reading and writing [21Neef NE, Müller B, Liebig J, et al. Dyslexia risk gene relates to representation of sound in the auditory brainstem. Dev Cogn Neurosci 2017; 24: 63-71.
[http://dx.doi.org/10.1016/j.dcn.2017.01.008] [PMID: 28182973]
].

Furthermore, targeted knock down of other dyslexia susceptibility candidate genes (such as KIAA0319 and DCDC2) resulted in similar patterns of neuronal migration [22Paracchini S, Thomas A, Castro S, et al. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum Mol Genet 2006; 15(10): 1659-66.
[http://dx.doi.org/10.1093/hmg/ddl089] [PMID: 16600991]
-24Burbridge TJ, Wang Y, Volz AJ, et al. Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat. Neuroscience 2008; 152(3): 723-33.
[http://dx.doi.org/10.1016/j.neuroscience.2008.01.020] [PMID: 18313856]
]. Functional analyses of these variations have also been studied indicating that Kiaa 0319 is expressed during development of mouse and human fetal brain and is involved in neuronal migration for the formation of the cerebral neocortex [22Paracchini S, Thomas A, Castro S, et al. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum Mol Genet 2006; 15(10): 1659-66.
[http://dx.doi.org/10.1093/hmg/ddl089] [PMID: 16600991]
]. Knockdown rat model of Dcdc2 by RNAi gave different phenotypes in contrast to an earlier study, in that these rats cannot identify specific speech sounds from a continuous train of speech sounds but they did not have problem in discrimination of isolated speech sounds [25Centanni TM, Booker AB, Chen F, et al. Knockdown of Dyslexia-Gene Dcdc2 interferes with speech sound discrimination in continuous streams. J Neurosci 2016; 36(17): 4895-906.
[http://dx.doi.org/10.1523/JNEUROSCI.4202-15.2016] [PMID: 27122044]
]. The mechanism of the effect of DCDC2 in neurodevelopmental disorder might be due to its function as one of the genes important in the formation of primary cilia, which could lead to determination of visceral asymmetry and brain lateralization [26Trulioff A, Ermakov A, Malashichev Y. Primary cilia as a possible link between left-right asymmetry and neurodevelopmental diseases. genes (Basel) 2017; 8(2): E48.
[http://dx.doi.org/10.3390/genes8020048] [PMID: 28125008]
, 27Tammimies K, Bieder A, Lauter G, et al. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs. FASEB J 2016; 30(10): 3578-87.
[http://dx.doi.org/10.1096/fj.201500124RR] [PMID: 27451412]
].

Other genes on chromosome 6p21 region have also been explored. An American group [28Marino C, Meng H, Mascheretti S, et al. DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatr Genet 2012; 22(1): 25-30.
[http://dx.doi.org/10.1097/YPG.0b013e32834acdb2] [PMID: 21881542]
, 29Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
]followed up their previous study [30Kaplan DE, Gayán J, Ahn J, et al. Evidence for linkage and association with reading disability on 6p21.3-22. Am J Hum Genet 2002; 70(5): 1287-98.
[http://dx.doi.org/10.1086/340449] [PMID: 11951179]
] and refined the 1.5Mb region by a high density marker panel of 147 SNPs. In their results, the strongest association (p ≤ 0.01) with discriminant score (DISC) phenotype was shown at the SNPs (rs807724 and rs1087266) of DCDC2 gene. In particular, reading skills were found to be associated with DCDC2 in a group of children born in England [31Scerri TS, Morris AP, Buckingham L-L, et al. DCDC2, KIAA0319 and CMIP are associated with reading-related traits. Biol Psychiatry 2011; 70(3): 237-45.
[http://dx.doi.org/10.1016/j.biopsych.2011.02.005] [PMID: 21457949]
]. Meng’s group also found a 2,445bp deletion polymorphism located in intron 2 also harboring a compound short tandem repeat (STR) polymorphism. The STR comprised of 10 alleles containing variable copy numbers of (GAGAGGAAGGAAA)n and (GGAA)n repeat units (named as “READ1” or “regulatory element associated with dyslexia 1” [32Powers NR, Eicher JD, Butter F, et al. Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment. Am J Hum Genet 2013; 93(1): 19-28.
[http://dx.doi.org/10.1016/j.ajhg.2013.05.008] [PMID: 23746548]
, 33Powers NR, Eicher JD, Miller LL, et al. The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles. J Med Genet 2016; 53(3): 163-71.
[http://dx.doi.org/10.1136/jmedgenet-2015-103418] [PMID: 26660103]
]). By combining the deletion and 10 minor alleles, a significant association was found with homonym choice phenotype [29Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
]. The deletion polymorphism, dbSTS ID no. 808238, encodes multiple copies of PEA3 and NF-ATp sites that are active in brain, and it was hypothesized that large deletion of this region which was found in dyslexics reported by Meng et al, would have a profound effect on DCDC2 function [29Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
]. The deletion present in Chinese occurs at a much higher allele frequency (0.384) than in other populations: US (0.085), German (0.086) and Italy (0.067) [16Ludwig KU, Schumacher J, Schulte-Körne G, et al. Investigation of the DCDC2 intron 2 deletion/compound short tandem repeat polymorphism in a large German dyslexia sample. Psychiatr Genet 2008; 18(6): 310-2.
[http://dx.doi.org/10.1097/YPG.0b013e3283063a78] [PMID: 19018237]
, 23Meng H, Smith SD, Hager K, et al. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005; 102(47): 17053-8.
[http://dx.doi.org/10.1073/pnas.0508591102] [PMID: 16278297]
, 28Marino C, Meng H, Mascheretti S, et al. DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatr Genet 2012; 22(1): 25-30.
[http://dx.doi.org/10.1097/YPG.0b013e32834acdb2] [PMID: 21881542]
].

The aim of our study was to find out if there are any association of genetic variants of DCDC2 with developmental dyslexia in the Chinese children from Hong Kong. To address this question, we use both genotyping with SNPs as well as deletion polymorphisms and in particular the dbSTS ID no.l 808238 that have been described by Meng’s reports.

2. MATERIALS AND METHODS

The procedures of subject recruitment, characteristics, and DNA extraction methodology has been reported previously in our earlier reports [3Lim CK, Ho CS, Chou CH, Waye MM. Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children. Behav Brain Funct 2011; 7: 16.
[http://dx.doi.org/10.1186/1744-9081-7-16] [PMID: 21599957]
, 20Lim CK, Wong AM, Ho CS, Waye MM. A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children. Behav Brain Funct 2014; 10: 23.
[http://dx.doi.org/10.1186/1744-9081-10-23] [PMID: 25015435]
, 34Rao S, Lee YN, Lim CK, Yeung VS, Ho CS, Baum L, et al. Association of ROBO1 polymorphism rs6803202 with developmental dyslexia in southern Chinese children. J Biochem Mol Biol Post Genomic Era 2016; 3: 31-8.]. In this study, 54 trios aged between 5 and 16 years were used. Subjects were diagnosed as DD cases using the Hong Kong Test of Specific Learning Difficulties in Reading and Writing (HKT-SpLD) [35The Chinese University of Hong Kong DW, Tsang, Education and Manpower Bureau, Hong Kong SAR Government S-M, Lee, Education and Manpower Bureau, Hong Kong SAR Government S-H. The Hong Kong Test of Specific Learning Difficulties in Reading and Writing. The Hong Kong Specific Learning Difficulties Behaviour Checklist. http://web.hku.hk/~hksld/homepage_e/group_e3.html 2000. accessed June 18, 2017] and referred by the local education authority, child assessment centres, and a parent association named Hong Kong Association for Specific Learning Disabilities. The HKT-SpLD battery consisted of 12 subtests. The subtests were broken down into three literacy tests, which are Chinese Word Reading (CWR), One-minute Reading (OMR) and Chinese Word Dictation (CWD), and one rapid naming test (DRN), where subjects were asked to name digits. Two subtests involve phonological awareness which is based on testing the subjects’ awareness of onsets (OD) and rhymes (RD) of Chinese syllables, and three were phonological memory subtests, where subjects were asked to repeat orally the syllables presented to them from a disc player, i.e. (Word Repetition I (WPI), Non-word Repetition (NWR), Word repetition II (WRII). The final three subtests were tests of orthographic skills. These tests consist of 70 simple Chinese integrated characters and Arabic numbers. Half of them were left/right reversed and the subjects were asked to cross out all items with an incorrect orientation, i.e., Left-Right Reversal (LRR). The subjects were asked to decide characters vs. non-characters, i.e., Lexical Decision (LD) and to identify the correct position of orthographic radicals in Chinese characters, i.e., Radical Position (RP).

These 12 subtests were combined to yield five composite scores in the domains of literacy, phonological awareness, phonological memory, rapid naming and orthographic skills. To be classified as children with dyslexia, their literacy composite score and at least one cognitive composite score had to be at least one standard deviation (SD = 3) below the means (mean = 10) of their respective ages in the HKT-SpLD (cutoff score = 7). Participants in the dyslexic group fulfilled this diagnostic criterion and all of the subjects showed a normal intelligence score on Raven’s Standard Progressive Matrices (with IQs of 85 or above). Saliva samples were first obtained from the participants in the dyslexic group. DNA samples were then extracted from these samples using the OrageneTM DNA self-collection kit following the manufacturer’s instructions (DNA Genotek, Inc., Ottawa, Canada). Permutation test (1000 runs) was used to run multiple testing corrections over all tests performed in single-marker association analyses of categorical DD.

Linkage disequilibrium (LD) was calculated and LD plots were generated using Haploview version 4.1 (http://www.broad.mit.edu/mpg/haploview) [36Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21(2): 263-5.
[http://dx.doi.org/10.1093/bioinformatics/bth457] [PMID: 15297300]
]. Odds ratio was estimated using the UNPHASED software for discrete analysis (affection status: diagnosed as dyslexia or not). For quantitative traits analysis, additive genetic value (AddVal) was estimated using the UNPHASED software, showing that the value shows the change in expected trait value due to the haplotype of interest relative to the reference haplotype selected. AddVal assumes a normally distributed trait and small deviations from the mean. Gene-gene interactions were analyzed using haplotype-based analysis with the UNPHASED software. The approach compares null hypothesis of equal contributions for all gene combinations in haplotype form sharing the same alleles at the conditioning marker to alternative hypothesis that is differential multiplicative contributions from the test marker. Chi-square tests were used for statistical analyses.

3. RESULTS

3.1. Association of DCDC2 with Chinese Dyslexic Children

The most significant marker was rs6940827 associated with DD with nominal p-value (0.011). However, this marker did not remain significant after multiple testing corrections and the adjusted p-value from permutation test was 0.1329 Table (1). Using sliding window haplotype analysis, several haplotypes were found to be nominally associated with DD. The smallest nominal p value was 0.0036 (rs2996452-rs1318700, C-A) Table (2). Given an ordered set of markers (1, 2....n), sliding windows of overlapping haplotypes were tested in sequence, i.e. markers 1-2 were treated as a single haplotype, then markers 2-3 were treated as a single haplotype, followed by markers 3-4, etc. Haplotypes of varying sizes (i.e. 2-, 3-SNP haplotypes, etc.) were assessed. However, none of the p values could withdraw the multiple testing corrections. Quantitative traits analysis was also performed and the nominal significant markers as shown in Table (3). Again, none of the markers could withdraw the multiple testing corrections.

Table 1
Single-marker analysis between SNPs of DCDC2 and categorical DD.


Table 2
Results of the haplotype analysis using 2- or 3-markers sliding window in markers of DCDC2 gene.


Table 3
Quantitative analysis of DCDC2 single SNP markers in HKT-SpLD tests. Only markers with nominal p values < 0.05 are shown.


3.2. Gene-Gene Interaction Analysis

Since a German group has found some interactions between DCDC2 and KIAA0319 in a large German dyslexia sample [18Ludwig KU, Roeske D, Schumacher J, et al. Investigation of interaction between DCDC2 and KIAA0319 in a large German dyslexia sample. J Neural Transm (Vienna) 2008; 115(11): 1587-9.
[http://dx.doi.org/10.1007/s00702-008-0124-6] [PMID: 18810304]
], we also attempted to find similar interactions. The significant haplotype rs2760157-rs807507 of KIAA0319 found in our previous study [20Lim CK, Wong AM, Ho CS, Waye MM. A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children. Behav Brain Funct 2014; 10: 23.
[http://dx.doi.org/10.1186/1744-9081-10-23] [PMID: 25015435]
] was used for testing gene-gene interaction with DCDC2. SNP-haplotype testing between rs2760157-rs807507 and each SNP of DCDC2 studied was evaluated for DD as well as for each reading related trait. As shown in Table (4), there was only a nominal significant gene-gene interaction between KIAA0319 and DCDC2. The associations did not remain significant after permutation tests.

Table 4
Test of interaction between KIAA0319 and DCDC2.


The DCDC2 deletion polymorphisms were studied by Sanger Dideoxy sequencing, using primers described previously [23Meng H, Smith SD, Hager K, et al. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005; 102(47): 17053-8.
[http://dx.doi.org/10.1073/pnas.0508591102] [PMID: 16278297]
, 29Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
]. We have used parents with heterozygous alleles for the calculation of disequilibrium of transmission (QTDT analyses) of the risk allele, and the total number of families used for the calculation was 54 out of a total number of 92 families. There was no significant association of known risk allele with dyslexia status and any subtest of the dyslexic scores, when the deletion risk allele (i.e. dbSTS ID no. 808238) was analyzed separately, and when the deletion allele and all remaining minor alleles of dbSTS ID no. 808238 were combined for analyses (*Allele 30). This may be due to the fact that the allele frequency of the deletion polymorphism (listed as allele 14 in Table (5) was higher which is very different from those reported for Caucasians.

Table 5
Alleles and frequencies of the compound STR, dbSTS ID 808238.


4. DISCUSSION

The prevalence rate of developmental dyslexia in Hong Kong Chinese school-aged children was estimated to be between 9.7% and 12.6% [37Chan DW, Ho CS, Tsang S, Lee S, Chung KK. Prevalence, gender ratio and gender differences in reading‐related cognitive abilities among Chinese children with dyslexia in Hong Kong. Educ Stud 2007; 33: 249-65.
[http://dx.doi.org/10.1080/03055690601068535]
], similar to the rate in Caucasian populations [38Flannery KA, Liederman J, Daly L, Schultz J. Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias. J Int Neuropsychol Soc 2000; 6(4): 433-42.
[http://dx.doi.org/10.1017/S1355617700644016] [PMID: 10902412]
]. Due to the significant impact of poor reading and writing on performance of students and the strong sense of competition in Chinese education, study of the genetic component of dyslexia is therefore important. Chinese language is known to be substantially different from Western languages, being logographic and morphosyllabic rather than being alphabetic and phonemic [39Ho CS, Bryant P. Learning to read chinese beyond the logographic phase. Read Res Q 1997; 32: 276-89.
[http://dx.doi.org/10.1598/RRQ.32.3.3]
]. Moreover, orthographic (rather than phonological) deficits were found to be the main problem for Chinese people with dyslexia, in contrast to Caucasians [40Ho CS, Chan DW, Lee S-H, Tsang S-M, Luan VH. Cognitive profiling and preliminary subtyping in Chinese developmental dyslexia. Cognition 2004; 91(1): 43-75.
[http://dx.doi.org/10.1016/S0010-0277(03)00163-X] [PMID: 14711491]
]. Functional MRI studies of Chinese people with dyslexia also revealed different biological abnormalities in their brains [41Siok WT, Perfetti CA, Jin Z, Tan LH. Biological abnormality of impaired reading is constrained by culture. Nature 2004; 431(7004): 71-6.
[http://dx.doi.org/10.1038/nature02865] [PMID: 15343334]
, 42Siok WT, Niu Z, Jin Z, Perfetti CA, Tan LH. A structural-functional basis for dyslexia in the cortex of chinese readers. Proc Natl Acad Sci USA 2008; 105(14): 5561-6.
[http://dx.doi.org/10.1073/pnas.0801750105] [PMID: 18391194]
]. Furthermore, altered topological organization of brain structural network showed that dyslexic children exhibited increased local efficiency combined with a tendency of decreased global efficiency and the general prolonged characteristic path length (which might be mainly caused by developmental abnormality of several white matter connections [43Vandermosten M, Boets B, Wouters J, Ghesquière P. A qualitative and quantitative review of diffusion tensor imaging studies in reading and dyslexia. Neurosci Biobehav Rev 2012; 36(6): 1532-52.
[http://dx.doi.org/10.1016/j.neubiorev.2012.04.002] [PMID: 22516793]
]) compared to that of control children, which is somewhat similar to those features observed in congenital amusia Madarin-speaking children of Beijing [44Zhao Y, Chen X, Zhong S, et al. Abnormal topological organization of the white matter network in Mandarin speakers with congenital amusia. Sci Rep 2016; 6: 26505.
[http://dx.doi.org/10.1038/srep26505] [PMID: 27211239]
]. Different laboratories have reported conflicting results related to the association of developmental dyslexia with DCDC2, our results, as shown below (Table 5), do not indicate a significant association but rather a nominally significant association only. This could be due to heterogeneity of samples of dyslexia due to different genes responsible for the phenotype or other involvement of unknown gene-environment interactions [45Mascheretti S, Bureau A, Battaglia M, et al. An assessment of gene-by-environment interactions in developmental dyslexia-related phenotypes. Genes Brain Behav 2013; 12(1): 47-55.
[http://dx.doi.org/10.1111/gbb.12000] [PMID: 23176554]
] or some other transcriptional regulatory factors of DCDC2 [27Tammimies K, Bieder A, Lauter G, et al. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs. FASEB J 2016; 30(10): 3578-87.
[http://dx.doi.org/10.1096/fj.201500124RR] [PMID: 27451412]
]. For example, an Italian-Canadian collaboration on DCDC2 and environmental factors (smoke and miscarriage) underlie attention deficit/hyperactivity disorder traits suggested a potential pleiotropic effect as revealed by a twin study [46Mascheretti S, Trezzi V, Giorda R, et al. Complex effects of dyslexia risk factors account for ADHD traits: evidence from two independent samples. J Child Psychol Psychiatry 2017; 58(1): 75-82.
[http://dx.doi.org/10.1111/jcpp.12612] [PMID: 27501527]
]. DCDC2 gene polymorphisms have been associated with dyslexia in Chinese Uyghur children [47Chen Y, Zhao H, Zhang Y-X, Zuo P-X. DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children. Neural Regen Res 2017; 12(2): 259-66.
[http://dx.doi.org/10.4103/1673-5374.200809] [PMID: 28400808]
]. Other model system did show a role of DCDC2 in other aspects of learning which might affect children's language ability. For example, genes targeting Dcdc2 in the knockdown rat model, impairments of long term memory and visual-spatial performance were reported [48Gabel LA, Marin I, LoTurco JJ, et al. Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice. Genes Brain Behav 2011; 10(8): 868-75.
[http://dx.doi.org/10.1111/j.1601-183X.2011.00727.x] [PMID: 21883923]
]. Knockdown of DCDC2 was related to a reduction in speech sound discrimination in a continuous stream in rat [21Neef NE, Müller B, Liebig J, et al. Dyslexia risk gene relates to representation of sound in the auditory brainstem. Dev Cogn Neurosci 2017; 24: 63-71.
[http://dx.doi.org/10.1016/j.dcn.2017.01.008] [PMID: 28182973]
]. Recently it was reported that mutation of the Dcdc2 leads to enhancement of the glutamatergic synaptic transmission between layer 4 neurons in mouse neocortex [49Che A, Truong DT, Fitch RH, LoTurco JJ. Mutation of the dyslexia-associated gene dcdc2 enhances glutamatergic synaptic transmission between layer 4 neurons in mouse neocortex. Cereb Cortex 2016; 26(9): 3705-18.
[http://dx.doi.org/10.1093/cercor/bhv168] [PMID: 26250775]
]. A summary of our findings is provided in (Table 6).

Table 6
Summary of results.


CONCLUSION

In conclusion, despite early findings that DCDC2 is a strong candidate for developmental dyslexia and that some of the genetic variants have been linked to brain structure and functions in several populations [23Meng H, Smith SD, Hager K, et al. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005; 102(47): 17053-8.
[http://dx.doi.org/10.1073/pnas.0508591102] [PMID: 16278297]
, 28Marino C, Meng H, Mascheretti S, et al. DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatr Genet 2012; 22(1): 25-30.
[http://dx.doi.org/10.1097/YPG.0b013e32834acdb2] [PMID: 21881542]
, 29Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
, 50Schumacher J, Anthoni H, Dahdouh F, et al. Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am J Hum Genet 2006; 78(1): 52-62.
[http://dx.doi.org/10.1086/498992] [PMID: 16385449]
-54Marino C, Scifo P, Della Rosa PA, et al. The DCDC2/intron 2 deletion and white matter disorganization: focus on developmental dyslexia. Cortex 2014; 57: 227-43.
[http://dx.doi.org/10.1016/j.cortex.2014.04.016] [PMID: 24926531]
], our findings show that DCDC2 is not strongly associated with dyslexia in Hong Kong Chinese, consistent with the reports from some other groups [16Ludwig KU, Schumacher J, Schulte-Körne G, et al. Investigation of the DCDC2 intron 2 deletion/compound short tandem repeat polymorphism in a large German dyslexia sample. Psychiatr Genet 2008; 18(6): 310-2.
[http://dx.doi.org/10.1097/YPG.0b013e3283063a78] [PMID: 19018237]
, 55Venkatesh SK, Siddaiah A, Padakannaya P, Ramachandra NB. Analysis of genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in Indian population. J Hum Genet 2013; 58(8): 531-8.
[http://dx.doi.org/10.1038/jhg.2013.46] [PMID: 23677054]
] and other meta-analyses studies [56Müller B, Wilcke A, Czepezauer I, Ahnert P, Boltze J, Kirsten H. Association, characterisation and meta-analysis of SNPs linked to general reading ability in a German dyslexia case-control cohort. Sci Rep 2016; 6: 27901.
[http://dx.doi.org/10.1038/srep27901] [PMID: 27312598]
]. In contrast to the meta-analyses carried out by Zhong’s group, our findings also do not support their conclusion that rs807701 is associated with developmental dyslexia [57Zhong R, Yang B, Tang H, et al. Meta-analysis of the association between DCDC2 polymorphisms and risk of dyslexia. Mol Neurobiol 2013; 47(1): 435-42.
[http://dx.doi.org/10.1007/s12035-012-8381-7] [PMID: 23229871]
]. However, our results cannot be generalized to all logographical languages as we have only included Hong Kong dyslexic children in this study. Future studies might consider studying FAM65B and CMAHP as new candidate genes in the DYX2 region [9Eicher JD, Powers NR, Miller LL, et al. Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ. Hum Genet 2014; 133(7): 869-81.
[http://dx.doi.org/10.1007/s00439-014-1427-3] [PMID: 24509779]
]; further expression studies using immortalized lymphocytes to correlate the expression of DCDC2 with genotypes, similar to other studies [58Lerer E, Levi S, Israel S, et al. Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study. Autism Res 2010; 3(6): 293-302.
[http://dx.doi.org/10.1002/aur.156] [PMID: 21182206]
] would also be important for further confirmation of our results.

ETHICAL STATEMENT

This study was approved by the ethical committee of The Chinese University of Hong Kong.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No Animals/Humans were used for studies that are base of this research.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Donation from the Croucher Foundation has made the early part of this study possible. We thank Ms PS Ma for her contribution in the analyses of the DCDC2 genotypes, and all the children and parents who have donated their saliva for this study. We thank Ms Venus Yeung for her technical assistance. The help from the Association of learning Disability and the Hong Kong Children Assessment Centre is much appreciated.

REFERENCES

[1] Taipale M, Kaminen N, Nopola-Hemmi J, et al. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci USA 2003; 100(20): 11553-8.
[http://dx.doi.org/10.1073/pnas.1833911100] [PMID: 12954984]
[2] Grigorenko EL. Developmental dyslexia: an update on genes, brains, and environments. J Child Psychol Psychiatry 2001; 42(1): 91-125.
[http://dx.doi.org/10.1111/1469-7610.00704] [PMID: 11205626]
[3] Lim CK, Ho CS, Chou CH, Waye MM. Association of the rs3743205 variant of DYX1C1 with dyslexia in Chinese children. Behav Brain Funct 2011; 7: 16.
[http://dx.doi.org/10.1186/1744-9081-7-16] [PMID: 21599957]
[4] Currier TA, Etchegaray MA, Haight JL, Galaburda AM, Rosen GD. The effects of embryonic knockdown of the candidate dyslexia susceptibility gene homologue Dyx1c1 on the distribution of GABAergic neurons in the cerebral cortex. Neuroscience 2011; 172: 535-46.
[http://dx.doi.org/10.1016/j.neuroscience.2010.11.002] [PMID: 21070838]
[5] Rosen GD, Bai J, Wang Y, et al. Disruption of neuronal migration by RNAi of Dyx1c1 results in neocortical and hippocampal malformations. Cereb Cortex 2007; 17(11): 2562-72.
[http://dx.doi.org/10.1093/cercor/bhl162] [PMID: 17218481]
[6] Szalkowski CE, Fiondella CG, Galaburda AM, Rosen GD, Loturco JJ, Fitch RH. Neocortical disruption and behavioral impairments in rats following in utero RNAi of candidate dyslexia risk gene Kiaa0319. Int J Dev Neurosci 2012; 30(4): 293-302.
[http://dx.doi.org/10.1016/j.ijdevneu.2012.01.009] [PMID: 22326444]
[7] Threlkeld SW, McClure MM, Bai J, et al. Developmental disruptions and behavioral impairments in rats following in utero RNAi of Dyx1c1. Brain Res Bull 2007; 71(5): 508-14.
[http://dx.doi.org/10.1016/j.brainresbull.2006.11.005] [PMID: 17259020]
[8] Deffenbacher KE, Kenyon JB, Hoover DM, et al. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: Linkage and association analyses. Hum Genet 2004; 115(2): 128-38.
[http://dx.doi.org/10.1007/s00439-004-1126-6] [PMID: 15138886]
[9] Eicher JD, Powers NR, Miller LL, et al. Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ. Hum Genet 2014; 133(7): 869-81.
[http://dx.doi.org/10.1007/s00439-014-1427-3] [PMID: 24509779]
[10] Grigorenko EL, Wood FB, Golovyan L, Meyer M, Romano C, Pauls D. Continuing the search for dyslexia genes on 6p. Am J Med Genet B Neuropsychiatr Genet 2003; 118B(1): 89-98.
[http://dx.doi.org/10.1002/ajmg.b.10032] [PMID: 12627473]
[11] Grigorenko EL, Wood FB, Meyer MS, et al. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am J Hum Genet 1997; 60(1): 27-39.
[PMID: 8981944]
[12] Gayán J, Smith SD, Cherny SS, et al. Quantitative-trait locus for specific language and reading deficits on chromosome 6p. Am J Hum Genet 1999; 64(1): 157-64.
[http://dx.doi.org/10.1086/302191] [PMID: 9915954]
[13] Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC. Quantitative trait locus for reading disability on chromosome 6. Science 1994; 266(5183): 276-9.
[http://dx.doi.org/10.1126/science.7939663] [PMID: 7939663]
[14] Petryshen TL, Kaplan BJ, Liu MF, Field LL. Absence of significant linkage between phonological coding dyslexia and chromosome 6p23-21.3, as determined by use of quantitative-trait methods: Confirmation of qualitative analyses. Am J Hum Genet 2000; 66(2): 708-14.
[http://dx.doi.org/10.1086/302764] [PMID: 10677330]
[15] Fisher SE, Francks C, Marlow AJ, et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nat Genet 2002; 30(1): 86-91.
[http://dx.doi.org/10.1038/ng792] [PMID: 11743577]
[16] Ludwig KU, Schumacher J, Schulte-Körne G, et al. Investigation of the DCDC2 intron 2 deletion/compound short tandem repeat polymorphism in a large German dyslexia sample. Psychiatr Genet 2008; 18(6): 310-2.
[http://dx.doi.org/10.1097/YPG.0b013e3283063a78] [PMID: 19018237]
[17] Lind PA, Luciano M, Wright MJ, Montgomery GW, Martin NG, Bates TC. Dyslexia and DCDC2: Normal variation in reading and spelling is associated with DCDC2 polymorphisms in an Australian population sample. Eur J Hum Genet 2010; 18(6): 668-73.
[http://dx.doi.org/10.1038/ejhg.2009.237] [PMID: 20068590]
[18] Ludwig KU, Roeske D, Schumacher J, et al. Investigation of interaction between DCDC2 and KIAA0319 in a large German dyslexia sample. J Neural Transm (Vienna) 2008; 115(11): 1587-9.
[http://dx.doi.org/10.1007/s00702-008-0124-6] [PMID: 18810304]
[19] Harold D, Paracchini S, Scerri T, et al. Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia. Mol Psychiatry 2006; 11(12): 1085-1091, 1061.
[http://dx.doi.org/10.1038/sj.mp.4001904] [PMID: 17033633]
[20] Lim CK, Wong AM, Ho CS, Waye MM. A common haplotype of KIAA0319 contributes to the phonological awareness skill in Chinese children. Behav Brain Funct 2014; 10: 23.
[http://dx.doi.org/10.1186/1744-9081-10-23] [PMID: 25015435]
[21] Neef NE, Müller B, Liebig J, et al. Dyslexia risk gene relates to representation of sound in the auditory brainstem. Dev Cogn Neurosci 2017; 24: 63-71.
[http://dx.doi.org/10.1016/j.dcn.2017.01.008] [PMID: 28182973]
[22] Paracchini S, Thomas A, Castro S, et al. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Hum Mol Genet 2006; 15(10): 1659-66.
[http://dx.doi.org/10.1093/hmg/ddl089] [PMID: 16600991]
[23] Meng H, Smith SD, Hager K, et al. DCDC2 is associated with reading disability and modulates neuronal development in the brain. Proc Natl Acad Sci USA 2005; 102(47): 17053-8.
[http://dx.doi.org/10.1073/pnas.0508591102] [PMID: 16278297]
[24] Burbridge TJ, Wang Y, Volz AJ, et al. Postnatal analysis of the effect of embryonic knockdown and overexpression of candidate dyslexia susceptibility gene homolog Dcdc2 in the rat. Neuroscience 2008; 152(3): 723-33.
[http://dx.doi.org/10.1016/j.neuroscience.2008.01.020] [PMID: 18313856]
[25] Centanni TM, Booker AB, Chen F, et al. Knockdown of Dyslexia-Gene Dcdc2 interferes with speech sound discrimination in continuous streams. J Neurosci 2016; 36(17): 4895-906.
[http://dx.doi.org/10.1523/JNEUROSCI.4202-15.2016] [PMID: 27122044]
[26] Trulioff A, Ermakov A, Malashichev Y. Primary cilia as a possible link between left-right asymmetry and neurodevelopmental diseases. genes (Basel) 2017; 8(2): E48.
[http://dx.doi.org/10.3390/genes8020048] [PMID: 28125008]
[27] Tammimies K, Bieder A, Lauter G, et al. Ciliary dyslexia candidate genes DYX1C1 and DCDC2 are regulated by Regulatory Factor X (RFX) transcription factors through X-box promoter motifs. FASEB J 2016; 30(10): 3578-87.
[http://dx.doi.org/10.1096/fj.201500124RR] [PMID: 27451412]
[28] Marino C, Meng H, Mascheretti S, et al. DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatr Genet 2012; 22(1): 25-30.
[http://dx.doi.org/10.1097/YPG.0b013e32834acdb2] [PMID: 21881542]
[29] Meng H, Powers NR, Tang L, et al. A dyslexia-associated variant in DCDC2 changes gene expression. Behav Genet 2011; 41(1): 58-66.
[http://dx.doi.org/10.1007/s10519-010-9408-3] [PMID: 21042874]
[30] Kaplan DE, Gayán J, Ahn J, et al. Evidence for linkage and association with reading disability on 6p21.3-22. Am J Hum Genet 2002; 70(5): 1287-98.
[http://dx.doi.org/10.1086/340449] [PMID: 11951179]
[31] Scerri TS, Morris AP, Buckingham L-L, et al. DCDC2, KIAA0319 and CMIP are associated with reading-related traits. Biol Psychiatry 2011; 70(3): 237-45.
[http://dx.doi.org/10.1016/j.biopsych.2011.02.005] [PMID: 21457949]
[32] Powers NR, Eicher JD, Butter F, et al. Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment. Am J Hum Genet 2013; 93(1): 19-28.
[http://dx.doi.org/10.1016/j.ajhg.2013.05.008] [PMID: 23746548]
[33] Powers NR, Eicher JD, Miller LL, et al. The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles. J Med Genet 2016; 53(3): 163-71.
[http://dx.doi.org/10.1136/jmedgenet-2015-103418] [PMID: 26660103]
[34] Rao S, Lee YN, Lim CK, Yeung VS, Ho CS, Baum L, et al. Association of ROBO1 polymorphism rs6803202 with developmental dyslexia in southern Chinese children. J Biochem Mol Biol Post Genomic Era 2016; 3: 31-8.
[35] The Chinese University of Hong Kong DW, Tsang, Education and Manpower Bureau, Hong Kong SAR Government S-M, Lee, Education and Manpower Bureau, Hong Kong SAR Government S-H. The Hong Kong Test of Specific Learning Difficulties in Reading and Writing. The Hong Kong Specific Learning Difficulties Behaviour Checklist. http://web.hku.hk/~hksld/homepage_e/group_e3.html 2000. accessed June 18, 2017
[36] Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21(2): 263-5.
[http://dx.doi.org/10.1093/bioinformatics/bth457] [PMID: 15297300]
[37] Chan DW, Ho CS, Tsang S, Lee S, Chung KK. Prevalence, gender ratio and gender differences in reading‐related cognitive abilities among Chinese children with dyslexia in Hong Kong. Educ Stud 2007; 33: 249-65.
[http://dx.doi.org/10.1080/03055690601068535]
[38] Flannery KA, Liederman J, Daly L, Schultz J. Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias. J Int Neuropsychol Soc 2000; 6(4): 433-42.
[http://dx.doi.org/10.1017/S1355617700644016] [PMID: 10902412]
[39] Ho CS, Bryant P. Learning to read chinese beyond the logographic phase. Read Res Q 1997; 32: 276-89.
[http://dx.doi.org/10.1598/RRQ.32.3.3]
[40] Ho CS, Chan DW, Lee S-H, Tsang S-M, Luan VH. Cognitive profiling and preliminary subtyping in Chinese developmental dyslexia. Cognition 2004; 91(1): 43-75.
[http://dx.doi.org/10.1016/S0010-0277(03)00163-X] [PMID: 14711491]
[41] Siok WT, Perfetti CA, Jin Z, Tan LH. Biological abnormality of impaired reading is constrained by culture. Nature 2004; 431(7004): 71-6.
[http://dx.doi.org/10.1038/nature02865] [PMID: 15343334]
[42] Siok WT, Niu Z, Jin Z, Perfetti CA, Tan LH. A structural-functional basis for dyslexia in the cortex of chinese readers. Proc Natl Acad Sci USA 2008; 105(14): 5561-6.
[http://dx.doi.org/10.1073/pnas.0801750105] [PMID: 18391194]
[43] Vandermosten M, Boets B, Wouters J, Ghesquière P. A qualitative and quantitative review of diffusion tensor imaging studies in reading and dyslexia. Neurosci Biobehav Rev 2012; 36(6): 1532-52.
[http://dx.doi.org/10.1016/j.neubiorev.2012.04.002] [PMID: 22516793]
[44] Zhao Y, Chen X, Zhong S, et al. Abnormal topological organization of the white matter network in Mandarin speakers with congenital amusia. Sci Rep 2016; 6: 26505.
[http://dx.doi.org/10.1038/srep26505] [PMID: 27211239]
[45] Mascheretti S, Bureau A, Battaglia M, et al. An assessment of gene-by-environment interactions in developmental dyslexia-related phenotypes. Genes Brain Behav 2013; 12(1): 47-55.
[http://dx.doi.org/10.1111/gbb.12000] [PMID: 23176554]
[46] Mascheretti S, Trezzi V, Giorda R, et al. Complex effects of dyslexia risk factors account for ADHD traits: evidence from two independent samples. J Child Psychol Psychiatry 2017; 58(1): 75-82.
[http://dx.doi.org/10.1111/jcpp.12612] [PMID: 27501527]
[47] Chen Y, Zhao H, Zhang Y-X, Zuo P-X. DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children. Neural Regen Res 2017; 12(2): 259-66.
[http://dx.doi.org/10.4103/1673-5374.200809] [PMID: 28400808]
[48] Gabel LA, Marin I, LoTurco JJ, et al. Mutation of the dyslexia-associated gene Dcdc2 impairs LTM and visuo-spatial performance in mice. Genes Brain Behav 2011; 10(8): 868-75.
[http://dx.doi.org/10.1111/j.1601-183X.2011.00727.x] [PMID: 21883923]
[49] Che A, Truong DT, Fitch RH, LoTurco JJ. Mutation of the dyslexia-associated gene dcdc2 enhances glutamatergic synaptic transmission between layer 4 neurons in mouse neocortex. Cereb Cortex 2016; 26(9): 3705-18.
[http://dx.doi.org/10.1093/cercor/bhv168] [PMID: 26250775]
[50] Schumacher J, Anthoni H, Dahdouh F, et al. Strong genetic evidence of DCDC2 as a susceptibility gene for dyslexia. Am J Hum Genet 2006; 78(1): 52-62.
[http://dx.doi.org/10.1086/498992] [PMID: 16385449]
[51] Wilcke A, Weissfuss J, Kirsten H, Wolfram G, Boltze J, Ahnert P. The role of gene DCDC2 in German dyslexics. Ann Dyslexia 2009; 59(1): 1-11.
[http://dx.doi.org/10.1007/s11881-008-0020-7] [PMID: 19238550]
[52] Cope N, Eicher JD, Meng H, et al. Variants in the DYX2 locus are associated with altered brain activation in reading-related brain regions in subjects with reading disability. Neuroimage 2012; 63(1): 148-56.
[http://dx.doi.org/10.1016/j.neuroimage.2012.06.037] [PMID: 22750057]
[53] Darki F, Peyrard-Janvid M, Matsson H, Kere J, Klingberg T. Three dyslexia susceptibility genes, DYX1C1, DCDC2, and KIAA0319, affect temporo-parietal white matter structure. Biol Psychiatry 2012; 72(8): 671-6.
[http://dx.doi.org/10.1016/j.biopsych.2012.05.008] [PMID: 22683091]
[54] Marino C, Scifo P, Della Rosa PA, et al. The DCDC2/intron 2 deletion and white matter disorganization: focus on developmental dyslexia. Cortex 2014; 57: 227-43.
[http://dx.doi.org/10.1016/j.cortex.2014.04.016] [PMID: 24926531]
[55] Venkatesh SK, Siddaiah A, Padakannaya P, Ramachandra NB. Analysis of genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in Indian population. J Hum Genet 2013; 58(8): 531-8.
[http://dx.doi.org/10.1038/jhg.2013.46] [PMID: 23677054]
[56] Müller B, Wilcke A, Czepezauer I, Ahnert P, Boltze J, Kirsten H. Association, characterisation and meta-analysis of SNPs linked to general reading ability in a German dyslexia case-control cohort. Sci Rep 2016; 6: 27901.
[http://dx.doi.org/10.1038/srep27901] [PMID: 27312598]
[57] Zhong R, Yang B, Tang H, et al. Meta-analysis of the association between DCDC2 polymorphisms and risk of dyslexia. Mol Neurobiol 2013; 47(1): 435-42.
[http://dx.doi.org/10.1007/s12035-012-8381-7] [PMID: 23229871]
[58] Lerer E, Levi S, Israel S, et al. Low CD38 expression in lymphoblastoid cells and haplotypes are both associated with autism in a family-based study. Autism Res 2010; 3(6): 293-302.
[http://dx.doi.org/10.1002/aur.156] [PMID: 21182206]

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"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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