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KIAA0319, a well-studied candidate gene, has been shown to be associated with reading ability and developmen- tal dyslexia. In the present study, we investigated whether KIAA0319 affects reading ability by interacting with the parental education level and whether rapid automatized naming (RAN), phonological awareness and morphologi- cal awareness mediate the relationship between KIAA0319 and reading ability. A total of 2284 Chinese children from primary school grades 3 and 6 participated in this study. Chinese character reading accuracy and word reading fluency were used as measures of reading abilities. The cumulative genetic risk score (CGS) of 13 SNPs in KIAA0319 was calculated. Results revealed interaction effect between CGS of KIAA0319 and parental education level on reading fluency. The interaction effect suggested that individuals with a low CGS of KIAA0319 were better at reading fluency in a positive environment (higher parental educational level) than individuals with a high CGS. Moreover, the interaction effect coincided with the differential susceptibility model. The results of the multiple mediator model revealed that RAN mediates the impact of the genetic cumulative effect of KIAA0319 on reading abilities. These findings provide evidence that KIAA0319 is a risk vulnerability gene that interacts with environmental factor to impact reading abilities and demonstrate the reliability of RAN as an endophenotype between genes and reading associations. Keywords KIAA0319, Reading ability, Rapid automatized naming, Differential susceptibility model, Gene-environment interaction phonological awareness, orthographic awareness, mor- Introduction pheme awareness and rapid automatized naming . It is Reading ability is a complex behavioral characteristic known that genetic variation accounts for 20–80% of the that mainly includes reading accuracy and reading flu - total variation in reading skills, and the genetic variations ency. The acquisition of reading skills are associated with discovered thus far only explain the “tip of the iceberg” of series of reading-related linguistic processes, such as estimated heritability [1, 2]. Among the susceptibility genes of reading dis/ability *Correspondence: identified to date, KIAA0319 is an important candidate Jingjing Zhao email@example.com gene. KIAA0319 affects neuronal migration, neurite out - Zhengjun Wang growth, cortical morphogenesis, and ciliary structure and firstname.lastname@example.org function [3–6]. Schmitz et al. analyzed DNA methylation School of Psychology, Shaanxi Normal University and Shaanxi Provincial Key Research Center of Child Mental and Behavioral Health, Yanta District, in the KIAA0319 promoter region to investigate whether 199 South Chang’an Road, Xi’an 710062, China epigenetic markers of language lateralization could be © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 2 of 13 identified in nonneuronal tissue . These data provide a the different responses of individuals in positive environ - framework to interpret the effects of the dyslexia-associ - ments . According to the differential susceptibility ated genetic variants that reside in KIAA0319 noncoding model, the same genetic traits or genotypes also have the regulatory regions . effect of making individuals better (for better) or worse Franks et al. used quantitative trait loci (QTL) analysis (for worse) under environmental factors . To explore and found that single nucleotide polymorphisms (SNPs) whether KIAA0319 should be considered a vulnerable or in KIAA0319 were associated with word reading, phono- plastic gene , the second aim of the present study was logical awareness, and orthographic rules . Moreover, to conduct interaction and competing model analyses to rs2143340 in KIAA0319 was replicated in the Avon Lon- examine which gene-environment model of the interac- gitudinal Study of Parents and Children (ALSPAC) and tion between KIAA0319 and parental education follows. found to be associated with poor performance of read- On the other hand, when studying the role of candidate ing and spelling . In subsequent studies, Scerri et al. genes, endophenotypes (EPs) can also reduce the effect found that rs2143340 was significantly correlated with of heterogeneity . Endophenotypes are more useful word reading accuracy in their quantitative analysis of than macroscopic behavior indicators and serve as medi- reading phenotypes . Quantitative analysis of samples ating variables for understanding complex pathways [28, from Dutch children with developmental dyslexia found 29]. EPs reflect neurophysiological, biochemical, endo - that rs761100 and rs2038137 in KIAA0319 were related crinological, cognitive or neuropsychological processes to digit rapid automatized naming, and that rs6935076 that are associated with traits or diseases and may reflect in KIAA0319 was related to word reading fluency . specific genes that are associated with behavioral pheno - However, there were also studies reporting no significant types [30–32]. relationship between KIAA0319 and reading ability [13, Reading-related linguistic skills might be important 14]. EPs between candidate genes and reading abilities. Rapid These inconsistencies can be explained in part by het - automatized naming (RAN), a well-studied reading- erogeneity between studies, possibly due to the different related skill, has been widely used in studies of reading criteria for phenotypic assessment, age, sample size, pop- acquisition and has been found to be reliably related ulation genetic background, and environmental factors. to reading achievement [33, 34]. Several studies have On the one hand, environmental factors can influence identified RAN to be independent of reading and read - the probability of gene expression in behavior . ing-related cognitive processes, such as orthographic Studies have shown gene‒environment interactions processing, phonological awareness, and short-term on several environmental factors, e.g., the home literacy memory [35–37]. Moreover, RAN has been found to be environment (HLE), socioeconomic status (SES), the heritable. Genome-wide association studies reported the prenatal education, and computer game interventions effects of SNPs on RAN, and classical twin studies found [14, 16–18]. For example, the presence of an interac- heritability estimates ranging from 0.56 to 0.70 for RAN tion between maternal stress during pregnancy and the [38–42]. The latest results explored RAN as an endophe - rs12193738 polymorphism in KIAA0319 was shown to notype that mediates the association between genes and affect reading ability at 16 years of age . However, reading ability [14, 43]. Therefore, RAN was investigated one polymorphism cannot represent the variation in as a mediator between KIAA0319 and reading ability in gene function, and many variants with small effects can - the present study. not be detected. The cumulative genetic score (CGS) can Phonological awareness and morphological awareness be used to investigate the influence of multiple genetic have also found to contribute to the development of read- polymorphisms [19–22]. The CGS was combined into a ing ability and significantly predict word recognition and single score by assigning points (0, 1 or 2) according to reading speed [44–47]. However, as reading-related lin- the number of sensitive alleles . Using the CGS can guistic skills, no studies have explored the possibility of increase statistical power and model more variants on phonological awareness and morphological awareness a gene. Therefore, the first aim of the present study was as endophenotypes. The heritability estimates of pho - to use the CGS approach to explore whether the CGS of nological awareness and morphological awareness were KIAA0319 impacts reading ability by interacting with the 0.19–0.83 [40, 48, 49] and 0.44–0.55 , respectively. environmental factor of parental education level. Candidate gene studies have also discussed the associa- Nevertheless, three gene‒environment models (G × E) tion of KIAA0319 with phonological and morphological exist at present. The diathesis-stress model emphasizes awareness [51, 52]. Therefore, this study also aimed to that individuals with disease risk alleles or vulnerability investigate the mediating effects of phonological aware - genotypes have higher negative environmental sensitivity ness and morphological awareness as intermediate [24, 25]. The vantage sensitivity model aims to describe phenotypes. Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 3 of 13 In sum, we aimed to investigate 1) the effect of the Table 1 The interaction between the cumulative genetic scores of KIAA0319 and parental education on reading fluency KIAA0319 interaction with the environment on reading abilities (Fig. 1A); 2) which gene‒environmental inter- Parameter Gene(G) and environment(E) Main effects and action model better fits the G × E effect; and 3) whether main effects: Model 1 G × E interaction: Model 2 genes affect reading abilities through endophenotypes of rapid automatized naming, phonological awareness, and B 253.53 (10.34) 270.10 (12.70) morphological awareness (Fig. 1B). B −5.27 (0.73) −10.41 (2.40) B 0.51 (0.28) −1.20 (0.81) B – 0.53 (0.24) Materials and methods B −0.83 (0.07) −0.83 (0.07) Participants B −2.06 (1.60) −2.12 (1.60) A total of 2284 participants (primary school stu- R 0.085 0.088 dents from Shaanxi, Gansu and Inner Mongolia) were F 36.69 30.43 recruited. All participants were normal school-age stu- df 4, 1583 5, 1582 dents from grade 3 to grade 6 without any history of p < 0.0001 < .0001 mental illness. In this study, saliva samples were collected F vs. 1 – 4.991 (gene samples were extracted). Participants completed df – 1,1581 two reading tests, including Chinese character recog- p – 0.0256 nition task (N = 2270) and Chinese word reading flu - ency task (N = 2270), six reading-related linguistic tasks, including four rapid automatized naming tasks (digit, picture, color, and dice) and phonological awareness Genotyping and SNP selection and morphonological awareness tasks (N = from 1968 to An Illumina Asian Screening Array (ASA, 700 K–750 K) 2244). chip was used for genotyping the obtained DNA sam- ples using the Beijing Compass biotechnology formula. PLINK was used to screen the following genotypes for standard quality control (Aderson et al., 2010; Chang, Fig. 1 The plot of the moderation effect of environment in genetic influence on reading-related phenotypes (A); the multiple mediation model plot of cognitive skills in gene-phenotype association (B) Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 4 of 13 2015): a single sample SNP detection rate higher than task is to remove a given phoneme from the syllable in 0.9 (sample call rate > 0.90); single SNP detection rates the word and speak out the rest of the syllable. The task (SNP call rate > 0.95); Hardy–Weinberg equilibrium coef- consists of 16 items: initial phoneme deletion items (e.g., –5 ficients (p < 10 ); minor allele frequencies (MAF > 0.01); /mei4/ (sister) without /m/), middle phoneme deletion and those with first degree of kinship was removed items (e.g., /tuan4/ (group) without /u/), and final pho - (PI_HAT > 0.50). MACH 4.0 software was used to carry neme deletion items (e.g., /guan1/ (close) without /n/). out full genome data (imputation) analysis based on the This task has been widely used in language studies of Asian population data in the Genome Asia Pilot (GAsp) Chinese children [46, 55, 56]. The reliability (Chronbach’s project, and the filled data were consistent with the pre - alpha) of the test was 0.90 . vious quality control standards. Thirteen SNPs were Morphological awareness task. Children are asked to extracted by PLINK v1.90. identify one of the morphemes among two-morpheme words and to create two new words with the target mor- Phenotypes pheme [55, 57]. One of the morphemes in a word has Reading uenc fl y (RF). Wordlist reading task [53, 54] was the same meaning as the target morpheme; conversely, used to measure each child’s reading fluency. In this task, one of the morphemes in the other word has a different children were asked to name a list of 180 two-character meaning. Presented with the word /bei1 bao1/ (which words as rapidly and accurately as possible. All these means backpack), children are asked to produce two new words were from primary school text books and have words containing /bao1/. In one word, /bao 1/ has the been learned before grade 3, such as “我们(we)” and “太 same meaning as /bei1 bao1/, such as /shu1 bao1/ (which 阳(sun)”. Since words included in this task were all sim- means bag). And in the other word, /bao 1/ is different ple, this task was administrated to test children’s reading from that of /bei1 bao1/, such as /bao1 zi1/ (which means fluency. The total time for naming the whole word list steamed stuffed bun). The Cronbach’s alpha of this ques - was recorded as measurement of reading fluency. tionnaire was 0.80 . Character recognition (CR): Chinese character rec- ognition test was used to measure each child’s reading Parental Education (PE) levels accuracy [53, 54]. The test consisted of 150 single Chi - A total of 1620 participants in this study had information nese characters selected from China’s Elementary School about their parents’ educational levels, with 1 represent- Textbooks (1996), with a reliability of 0.95 . Each ing the lowest educational level and 8 representing the child was individually tested and required to read aloud highest educational level: 1 = primary school education, each character at a time. 2 = junior high school education, 3 = senior high school Rapid automatized naming tasks. The rapid automa - education, 4 = junior college education, 5 = undergradu- tized naming tasks include four tasks: rapid automatized ate degree, 6 = master’s degree, 7 = doctoral degree, and naming of digits, pictures, colors, and dices . Four 8 = postdoc. The average score of mother’s and father’s series of 40 items (digits, pictures, dices, and colors) were educational levels was used as a child’s parental edu- presented to each child, with each type of items on a cational level. Finally, 1,588 children had data on both separate sheet of paper. The digits (2, 4, 6, 7, and 9) were character recognition and parental educational level, used as stimuli of rapid automatized digit naming task. and 1,589 children had data on both reading fluency and The pictures (dog, flower, book, shoe, and window) were parental educational level. used as stimuli of rapid automatized picture naming task. Pictures of dices (one, two, three, four, and five) were Data analysis used as stimuli of rapid automatized dice naming task. SNP coding and cumulative genetic scores (CGSs) The colors (red, yellow, black, green, and blue) were used The SNPs on KIAA0319 were reported in our recent as stimuli of rapid automatized color naming task. Each GWAS of dyslexia and were replicated in reading fluency sheet includes eight rows with five items in a row. Chil - in the Chinese sample [58, 80]. The sample of the current dren were required to name each type of items as rapidly study and the Chinese sample in Doust et al. were from as possible. Each child named twice for each sheet. The the same cohort . We therefore adopted the β values measurement of rapid automatized naming was the aver- for the phenotype of reading fluency and character rec - age naming times for the two times of each type of items. ognition from our Chinese sample in this study . The The test–retest reliabilities of rapid automatized digit, cumulative genetic score (CGS) of the KIAA0319 gene picture, dice, and color naming tasks were 0.87, 0.82, was calculated by combining risk alleles of the 13 SNPs. 0.74, and 0.74, respectively. Coding was based on the first allele and beta value. When Phonological awareness task. In this task, a child is the value of β was positive, the homozygous with the verbally presented with a one-syllable word. The child’s first allele was 2 and the heterozygous was 1, 0 was the Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 5 of 13 homozygous for the minor allele. When the beta value Z score according to separately each grade . All the was negative, it was opposite to the encoding genotype. predictor measures were allowed to be related to each other. Indirect effects were tested using the 5000 boot - Gene by Enviornment Interaction analysis strap technique , and confidence intervals (95% CIs) Stratified regression analysis was performed to explore that did not contain zero indicated significant indirect the interactions of 13 SNPs and the CGS with the paren- effects . We reported a variety of indices to reflect the tal education level. The standard multiple regression model fit . equation is as follows: Results Y = B0 + B1X1 + B2X2 + B3(X1 × X2) + B4 · Age + B5 · Sex + E Correlation analysis (1) The 13 SNPs conformed to Hardy–Weinberg equilib - where Y is the dependent variable (i.e., reading fluency); rium (Additional file 1: Table S1). Figure 2 presents the X is the environmental variable (PE); X is the genetic 1 2 correlation among variables for the total sample. Due to variable, X × X is the product term of the gene‒environ- 1 2 correlations between behavioral phenotypic variables, ment interaction; B and B are the regression slopes of 1 2 we adopted FDR correction (Benjaminiand Hochberg the main effects of environment X and gene X , respec- 1 2 correction) for multiple corrections to reduce the type tively; B is the regression coefficient of their interaction I error (Additional file 1: Table S2). The CGS of reading term; B is the intercept; and E is the random error. fluency (RF_CGS) was marginally correlated with reading fluency (r = 0.040, p = 0.06) and significantly correlated Reparameterized regression model tests with digit rapid automatized naming (r = 0.052, p = 0.02). The reparametric equation  is as follows: The CGS of character recognition (CR_CGS) were mar - ginally significantly correlated with color rapid automa - Y = B0 + B1(X1 − C) + B2((X1 − C) × X2) (2) tized naming (r = 0.053, p = 0.02). For the mean Z-score + B3 · Age + B4 · Sex + E of the four RAN tasks, it was significantly correlated with Equation 2 is a 5-parameter equation (i.e., B0, B1, B2, CR_CGS (r = 0.061, p = 0.007), and significantly corre - B3, B4, C). C is the intersection of the predicted values lated with RF_CGS (r = 0.055, p = 0.02). Reading fluency of the environmental variables of the two groups; if the and all of the rapid automatized naming tasks were sig- crossover of C and its confidence interval (CI) is within nificantly correlated. Moreover, there was no correlation the range of values in the environment, the interaction is between PE and genetic variables. disordinal, reflecting the differential susceptibility model, and if it falls outside the range, the interaction is ordinal Standard exploratory analysis and conforms to the diathesis-stress model . Standard regression equations were used to test the In this study, B1 is the slope of PE, and B2 is the slope G × E effect of a single SNP, CR_CGS (Additional file 1: of the interaction term. Point C is not fixed. If Point C Table S3 and Table S4) and RF_CGS (Table 1). In read- is within the range of the parental education level, the ing fluency and character recognition, no single SNP interaction of G × E conforms to the differential suscep - reached significance in the interaction terms after Bon - tibility model. If Point C is fixed, a crossover point that ferroni correction (adjusted-p: 0.05/13 = 0.0038). PE level falls at the maximum value of the environment variable was significant in all regression main effects. In Model 1 is added (C = Max (PE)). At this point, the interaction (Table 1), before adding the G × E interaction term, the of G × E is orderly and conforms to the diathesis-stress main effect of the PE level was significant (B = -5.27, model. ANOVA, the Akaike information criterion (AIC) p < 0.001), and the predicting effect of RF_CGS for read - and the Bayesian information criterion (BIC) were used ing fluency was not (B = 0.51, p = 0.07). In Model 2, to evaluate the two models. For the AIC and BIC, the the G × E effect was significant (B = 0.53, p = 0.026, lower the value is, the higher the efficiency of the model. R = 0.088). Simple slope analysis showed (Fig. 3A) that with the increase in the PE level, the time of reading flu - Mediation analysis ency of the low RF_CGS group was significantly faster The series of structural equation modeling (SEM) anal - than that of the high RF_CGS group. However, the inter- yses were conducted by using Mplus 17.0 to explore action between CR_CGS and the PE level did not predict whether rapid automatized naming, phonological aware- character recognition. ness, and morphological awareness mediate the effect of cumulative genetic scores on reading fluency and read - Competing test selection ing accuracy after controlling for age and sex. All the Reparameterized Eq. 2 was used to verify the interac- phenotypes and endophenotypes were transformed into tion between the KIAA0319 gene and parental education Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 6 of 13 Fig. 2 The heat map of Pearson correlation coefficient and p-value between CGS and behavioral phenotypic variables. CR_CGS: the cumulative genetic socre of KIAA0319 on character recognition, RF_CGS: the cumulative genetic socre of KIAA0319 on reading fluency, RF: reading fluency, CR: character recognition, PA: phonological awareness, MA: morphological awareness, R1: digit rapid automatized naming, R2: dice rapid automatized naming, R3: picture rapid automatized naming, R4: color rapid automatized naming, R.mean: the mean Z-score of four RANs, PE: parental education. *p < 0.05, **p < 0.01 Fig. 3 Simple slope analysis of reading fluency in the Low and High CGS subgroups (A); the plot for the results of the interaction between the CGS and PE level to predict reading fluency in the differential susceptibility model (B) Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 7 of 13 level. Table 2 shows that Model 3 (i.e., the differential sus - 0 (Model 5 in Table 4, Fig. 4A) and total indirect effect ceptibility model) had the best fitting effect on reading was significant (p = 0.021, 95% CI [0.001, 0.019]). fluency (Fig. 3B). Compared with Model 4, Model 3 had We further analyzed four RAN tasks as parallel medi- an estimated parameter added, and the interpretation ating variables. The results showed that the mediat - 2 2 rate of R increased significantly (△R = 0.004, p = 0.006), ing effect of digit RAN (p = 0.04, 95% CI [0.001, 0.041]) so Model 4 was rejected. Furthermore, by comparing and total indirect effect (p = 0.03, 95% CI [0.004, 0.056]) Model 3 and Model 4, the AIC and BIC of Model 4 were were significant in reading fluency (Model 6 in Table 4, both larger than those of Model 3, and Model 3b was Fig. 4B). Model 6 has a good model fit index: the CFI rejected. Overall, Model 3 had better fitting performance. (comparative fit index) = 1.000 > 0.90; the TLI (Tucker‒ In the G × E effect, RF_CGS and the parental education Lewis index) = 0.994 > 0.90; the RMSEA (root mean (PE) level fit the differential susceptibility model. square error of approximation) = 0.019 < 0.80; and χ /df = 1.90 < 3 (Table 3). According to the β values, the Test of the mediation model specific indirect effect pathways were positive. The result A series of structural equation modeling (SEM) analyses suggested that the higher the RF_CGS, the longer the were conducted to explore whether rapid automatized RAN time, and correspondingly, the longer the reading naming, phonological awareness, and morphological fluency time. awareness mediated the effect of the KIAA0319 gene on The mediation model from CR_CGS to character rec - reading fluency after controlling for sex and age (Fig. 4). ognition showed that there were also significant mediat - The indices of the Model 5 in Table 3 provided a good fit ing effects of RAN. Though the total indirect effect is not to the data: the CFI (comparative fit index) = 0.997 > 0.90; significant (p = 0.12, 95% CI [-0.034, 0.003]), the mediat- the TLI (Tucker‒Lewis index) = 0.981 > 0.90; the RMSEA ing effect of RAN (average Z score of the four RAN tasks) (root mean square error of approximation) = 0.024 < 0.80; was significant (Model 7 in Additional file 1: Table S5, and χ /df = 2.35 < 3. Using 5000 bootstrap analyses and Figure S1). In the separate RANs mediation model, the 95% CIs, we found that the significant mediation of RAN mediating effects of digit RAN (p = 0.03, 95% CI [-0.019, (average z score of the four RAN tasks) in reading fluency -0.002]) and picture RAN were significant (p = 0.01, 95% (p = 0.034), and the 95% CI [0.001, 0.017], did not include CI [0.004, 0.019]) (Model 8 in Additional file 1: Table S5, Figure S2). Table 2 Re-parameterized regression analysis Discussion Linear × Linear interaction The present study examined the cumulative effect of Parameter Differential susceptibility Diathesis- KIAA0319 on reading skills by a moderation effect of Model 3 Stress Model 4 parental educational level and a mediation effect of reading-related linguistic skills. The interaction between B 246.63 (9.70) 227.35 (8.24) individual SNPs in KIAA0319 and the parental educa- B −10.40 (2.40) −4.57 (1.16) tion level was not significant. However, the interaction B 0.52 (0.24) −0.07 (0.09) between the CGS of KIAA0319 and the parental educa- C 2.27 (0.68) 6.00 (–) tion level on reading fluency was significant, suggesting B −0.83 (0.07) -0.83 (0.07) that KIAA0319 may affect children’s reading abilities B −2.13 (1.60) −2.05 (1.60) through multiple minor effects. We also found that the R 0.0875 0.0831 CGS of KIAA0319 can affect children’s reading abilities F 31.85 31.92 through rapid automatized naming, mainly by digit rapid df 5,1581 4, 1582 automatized naming. Additionally, we built four moder- p < 0.0001 < 0.0001 ated mediation models according to the significant medi - F vs. 2 7.65 – ator variables and found that these models did not fit well df 1,1581 – (Additional file 1: Table S6 and Figure S3). These results p 0.006 – suggested that KIAA0319 influence behavioral pheno - AIC 15497.49 15503.15 types either through mediation model or moderation BIC 15535.08 15535.37 model independently. Tabled values are parameter estimates, with their standard errors in parentheses The present study is the first to assess the cumulative F vs 2, stands for an F test of the difference in R for Model 3 versus Model 4, effect of candidate gene KIAA0319 on reading ability in respectively Chinese children using the cumulative genetic risk score. AIC Akaike information criterion, BIC Bayesian information criterion As already noted, in most G × E work, one polymorphism Parameter fixed at maximum deviation; SE is not applicable, so is listed as (–) Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 8 of 13 Fig. 4 Significant specific indirect of the RAN effect from RF_CGS to reading fluency after controlling for sex and age (standardized estimates of the path coefficients are depicted in Model 5) (A); Significant specific indirect of the RAN effect from RF_CGS to reading fluency after controlling for sex and age (standardized estimates of the path coefficients are depicted in Model 6) (B).The model was adjusted because of the correlations between individual RAN (some path coefficients have been omitted for brevity). RAN: the mean Z-score of four RAN tasks is studied at a time. The CGS model accounts for more away and might be through complex and comprehensive variance than individual SNPs, which, to a certain extent, mediation processes, it is reasonable that the cumula- reduced the problem of repeated analysis of individual tive effect of KIAA0319 is very weak. This is indeed the polymorphisms . In present study, the cumulative reason that we should investigate the mediation pheno- effect of KIAA0319 only accounted for 0.1% variance and types that could explain the relations between genes and G × E effect accounted for 0.3% variance in reading flu - behaviors . ency. The pathway from gene to reading behavior is far Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 9 of 13 Table 3 Fitting index of KIAA0319_CGS on reading abilites of mediation model 2 2 χ df χ /df CFI TLI RMSEA Model 5 7.05 3 2.35 0.997 0.981 0.024 Model 6 3.80 2 1.90 1.000 0.994 0.019 Model 7 11.13 6 1.855 0.995 0.981 0.019 Model 8 15.33 6 2.56 0.997 0.987 0.017 CFI: Comparative Fit Index, TLI :Tucker-Lewis Index, RMSEA: Root Mean Square Error of Approximation. Model 5 refers to the mediation model of RF_CGS on phonological awareness, Morphological awareness and RAN. Model 6 refers to the mediation model of RF_CGS on RANs. Model 7 refers to the mediation model of CR_CGS on phonological awareness, morphological awareness and RAN. Model 8 refers to the mediation model of CR_CGS on RANs Table 4 Specific indirect effects of RANs, phonological awareness and morphological awareness from CGS to reading fluency. (Standardized βs and SEs are reported) β SE 95% CI* Model 5 Total indirect effect 0.030 0.013 [0.004, 0.055] RF_CGS → RAN → Reading fluency 0.025 0.011 [0.001, 0.017] RF_CGS → Phonological awareness → Reading fluency 0.001 0.002 [−0.001, 0.002] RF_CGS → Morphological awareness → Reading fluency 0.003 0.003 [−0.001, 0.003] Model 6 Total indirect effect 0.030 0.013 [0.004, 0.056] RF_CGS → Digit RAN → Reading fluency 0.021 0.010 [0.001, 0.041] RF_CGS → Dice RAN → Reading fluency 0.001 0.002 [−0.001, 0.006] RF_CGS → Picture RAN → Reading fluency 0.004 0.003 [−0.001, 0.012] RF_CGS → Color RAN → Reading fluency 0.003 0.002 [0.000, 0.008] Significant coefficients are reported in bold In terms of G × E, individuals with a low CGS were [25, 64] but not adverse environments . Although better at reading fluency in a positive environment than there have been some findings of vantage sensitivity individuals with a high CGS. These results suggested models in other domains, the study of cognitive abil- that the more risk alleles an individual carries, the worse ity has shown that the cumulative genetic scores of the their performance, and KIAA0319 is theoretically a vul- COMT and DRD2 genes and the effect of father authori - nerability gene. The G × E effect on reading fluency was tarianism on creativity are consistent with the vantage found to be consistent with the differential susceptibility sensitivity model , the evidence is lacking in the field model by competing model analysis. This result indicated of reading. Therefore, the results of the vantage sensitiv - that “vulnerability genes” can be appropriately described ity model need to be further validated. as “plastic genes” because they make individuals more Finally, our study also supports the mediating role of susceptible to environmental influences and thus exhibit digit RAN between KIAA0319 and reading abilities [47, better or worse behavior [23, 26]. In this study, the nega- 67]. For the first time, we found that the cumulative effect tive effects of KIAA0319 on reading ability were verified of KIAA0319 can affect Chinese word reading fluency for the first time through reparameterized regression and character recognition through RAN. The correlations models. In other words, the more risk alleles an indi- between the CGS and RAN were consistent with previous vidual carries, the more vulnerable they are, potentially results that KIAA0319 can affect RAN [12, 52]. Although causing irreversible harm, and the environment has little previous studies have also consistently reported RAN is effect on the individual. Conversely, individuals carrying an important predictor for Chinese reading accuracy  fewer vulnerability alleles are more susceptible to envi- and reading fluency [34, 69] as well as for reading abilities ronmental influences and thus perform well. in various orthographies [70–72], no study has examined To some extent, the finding is also consistent with the whether RAN can mediate a gene-reading association. vantage sensitivity model due to the small value of the The current research provided the first hand evidence cross point. The notion is that salutary environments can for RAN as a possible endophenotype between gene and moderate the influence of genetic variations on behaviors behavioral phenotype. Our data also suggest that digit Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 10 of 13 RAN might be the best RAN endophenotype among all whereas in our study, RAN was found to mediate gene- RAN tasks. This is consistent with previous behavioral phenotype associations. This might be due to different studies, in which digit RAN has been used more widely measurement methods of endophenotypes, different lan - than other RAN tasks in predicting reading abilities and guages and fewer selected SNPs in these studies. Second, dyslexia [55, 57, 73]. However, it should be noted that we used β values derived from the phenotype of reading we also found picture RAN can mediate KIAA0319 and abilities, so the individual variant and cumulative genetic reading accuracy, but not for reading fluency. This sug - scores encoded do not provide an accurate estimate of gests that other than digit RAN, sometimes picture RAN the effect on RAN. This independent cumulative effect might also be able to serve as a surrogate endophenotype. might affect the mediation effect of RAN, which means Previous studies have indicated that KIAA0319 was that, coincident with models of multiple deficits, the mainly expressed in the cerebral cortex, amygdala and influence of genetic variation in reading ability through cerebellum [74–76], suggested the alternative level of RAN, especially for rapid automatized naming tasks of KIAA0319 could be the cause of neuronal migration color and dice is limited [1, 86]. Third, we did not find abnormalities that might lead to the development of significant mediating effects of phonological awareness dyslexia. Furthermore, Jamadar et al. found a signifi - and morphological awareness. In this study we only used cant association between KIAA0139 and cerebellar gray phoneme deletion and morphological production to matter volume in dyslexic patients . Rapid automa- test phonological awareness and morphological aware- tized naming as an ability to retrieve familiar phono- ness. Future studies might be valuable to use other tasks logical information automatically is a reliable indicator (e.g., spoonerism, morphological judgment) to further of reading skills . Cerebellum theory of dyslexia  investigate whether phonological awareness and mor- provides a theoretical framework which indicates that phological awareness can mediate gene and reading as cerebellum might be a key to automatic decoding and endophenotypes. Finally, the SNPs we selected did not processing of words, which affects the accuracy and flu - show significant interaction effects. A possible reason ency of word reading . Recently, our GWAS study dis- is the insufficient statistical power, since the number of covered that EVC expression in the cerebellum affected samples verifying the interaction was more than the reading fluency, further supporting the cerebellar theory number of samples for which the effect was found alone . Thus, it is reasonable to speculate that the cumula - . The significant results of cumulative gene score tive effect might affect the expression of KIAA0319 in the might be the increased power of the cumulative effect, cerebellum, and in turn, impair the automated processing which should be replicated in an independent cohort to and reading speed. verify the interaction effects. Alternatively, KIAA0319 has also been found to associ- ate with the rapid auditory processing deficit of dyslexia Conclusion [3, 81]. The expression of KIAA0319 has been found to KIAA0139, a candidate gene for reading ability, is a risk influence the temporal lobe [74, 81, 82], whose biologi- factor of reading disability, not a protective factor. The cal signals may have an impact on the neuronal tempo- more risk alleles a person carries, the worse their read- ral coding, and in turn, impact the auditory processing. ing fluency is. The finding that KIAA0319 impacts read - Indeed, the rapid auditory processing deficit theory ing fluency by interacting with parental education level suggests that the individuals who are impaired in read- suggests that environmental variables can modulate the ing might be due to poor hearing for short and rapidly effects of KIAA0319 on children’s reading behaviors. changing sounds . Phoneme processing problems Individuals with a low CGS of KIAA0319 were better at might result from imprecise acoustic input encoding . reading fluency in a positive environment (higher paren - Hence, phonological impairment of dyslexia is actually tal educational level) than individuals with a high CGS. caused by rapid auditory processing deficit . There - In addition, the impact of the genetic cumulative effect of fore, an alternative explanation for the mediation effect KIAA0319 on reading abilities can be mediated by cogni- between KIAA0319, RAN, and reading might be that tive intermediate phenotypes of rapid automatized nam- KIAA0319 have an impact on the expression in tempo- ing. These findings provide evidence that KIAA0319 is a ral lobe and auditory processing, then further affect RAN risk vulnerability gene that interacts with environmental and reading. factor to impact reading abilities and demonstrate the There were several limitations in the current study. reliability of RAN as an endophenotype between gene First, contrary to our findings, previous studies did not and reading associations. provide sufficient evidence for RAN as an EP [43, 85], Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 11 of 13 3. Szalkowski CE, Fiondella CF, Truong DT, Rosen GD, LoTurco JJ, Fitch RH. Supplementary Information The effects of Kiaa0319 knockdown on cortical and subcortical anatomy The online version contains supplementary material available at https:// doi. in male rats. Int J Dev Neurosci. 2013;31(2):116–22. org/ 10. 1186/ s12993- 023- 00212-z. 4. Velayos-Baeza A, Levecque C, Kobayashi K, Holloway ZG, Monaco AP. The dyslexia-associated KIAA0319 protein undergoes proteolytic processing Additional file 1: Table S1. Characteristics of the single-nucleotide with γ-secretase-independent intramembrane cleavage*. J Biol Chem. polymorphismsof KIAA0319. Table S2. Correlation matrix of cumulative 2010;285(51):40148–62. genetic scores, cognitive skills, reading fluency, character recognition. 5. Peschansky VJ, Burbridge TJ, Volz AJ, Fiondella C, Wissner-Gross Z, Table S3. Results for standard parameterization models for 13 SNPs on Galaburda AM, Turco JJL, Rosen GD. The Eec ff t of variation in expression reading fluency. Table S4. Results for standard parameterization models of the candidate dyslexia susceptibility gene homolog Kiaa0319 on for 13 SNPs and CR_CGS on character recognition. Table S5. Specific neuronal migration and dendritic morphology in the rat. Cereb Cortex. indirect effects of RANs, phonological awareness and morphologi- 2009;20(4):884–97. cal awareness from CGS to character recognition in modified models. 6. Poon M-W, Tsang W-H, Chan S-O, Li H-M, Ng H-K, Waye MM-Y. Dyslexia- Table S6. Fitting index of cumulative genetic score of Reading fluency associated Kiaa0319-like protein interacts with axon guidance receptor on moderated mediation model. Figure S1. Significant specific indirect nogo receptor 1. Cell Mol Neurobiol. 2011;31(1):27–35. of the RAN effect from CR_CGS to character recognition after control- 7. Schmitz J, Kumsta R, Moser D, Güntürkün O, Ocklenburg S. KIAA0319 ling for sex and age. Figure S2. Significant specific indirect effects of the promoter DNA methylation predicts dichotic listening performance in digit RAN and picture RAN from CR_CGS to character recognition after forced-attention conditions. Behav Brain Res. 2018;337:1–7. controlling for sex and age. The model was adjusted for the correlations 8. Gostic M, Martinelli A, Tucker C, Yang Z, Gasparoli F, Ewart J-Y, Dholakia between different RAN tasks. Figure S3. The moderated-mediation model K, Sillar KT, Tello JA, Paracchini S. The dyslexia susceptibility KIAA0319 of Parental Education and RAN. gene shows a specific expression pattern during zebrafish develop - ment supporting a role beyond neuronal migration. J Comp Neurol. 2019;527(16):2634–43. Author contributions 9. Francks C, Paracchini S, Smith SD, Richardson AJ, Scerri TS, Cardon LR, JZ and ZW conceived of the presented idea. ZW, QY, and CC performed the Marlow AJ, MacPhie IL, Walter J, Pennington BF, et al. A 77-kilobase experiments and data analysis and assisted in writing the manuscript. QY, CC, region of chromosome 6p22.2 is associated with dyslexia in families from and ZW performed the experiments and analyzed the data. JZ, QY, and ZW the United Kingdom and from the United States. Am J Hum Genetics. designed the study and wrote the manuscript. All authors read and approved 2004;75(6):1046–58. the final manuscript. 10. Paracchini S, Steer CD, Buckingham L-L, Morris AP, Ring S, Scerri T, Stein J, Pembrey ME, Ragoussis J, Golding J. Association of the KIAA0319 dyslexia Funding susceptibility gene with reading skills in the general population. Am J This work was funded by National Natural Science Foundation of China Psychiatry. 2008;165(12):1576–84. (61807023), Funds for Humanities and Social Sciences Research of the Ministry 11. Scerri TS, Morris AP, Buckingham L-L, Newbury DF, Miller LL, Monaco AP, of Education (17XJC190010), Natural Science Foundation of Shaanxi Province Bishop DVM, Paracchini S. DCDC2, KIAA0319 and CMIP are associated (2018JQ8015 and 2023-JC-YB-703), and Fundamental Research Funds for the with reading-related traits. Biol Psychiatry. 2011;70(3):237–45. Central Universities (GK201702011) to Jingjing Zhao. This study was also sup- 12. Carrion-Castillo A, Maassen B, Franke B, Heister A, Naber M, van der Leij A, ported by Funds for Humanities and Social Sciences Research of the Ministry Francks C, Fisher SE. Association analysis of dyslexia candidate genes in a of Education (19YJC190023), the China Postdoctoral Science Foundation fund- Dutch longitudinal sample. Eur J Hum Genet. 2017;25(4):452–60. ing project (2019M663924XB), Natural Science Foundation of Shaanxi Province 13. Becker J, Czamara D, Scerri TS, Ramus F, Csépe V, Talcott JB, Stein J, Morris (2021JQ-309), and Planning Subject for the 14th Five Year Plan of Shaanxi A, Ludwig KU, Hoffmann P, et al. Genetic analysis of dyslexia candidate Education Sciences (SGH21Y0040) to Zhengjun Wang. genes in the European cross-linguistic NeuroDys cohort. Eur J Hum Genet. 2014;22(5):675–80. Availability of data and materials 14. Mascheretti S, Riva V, Giorda R, Beri S, Lanzoni LFE, Cellino MR, Marino C. Codes used in this study are available from the authors upon request. KIAA0319 and ROBO1: evidence on association with reading and pleio- tropic effects on language and mathematics abilities in developmental dyslexia. J Hum Genet. 2014;59(4):189–97. Declarations 15. Manuck SB, McCaffery JM. Gene-environment interaction. Annu Rev Psychol. 2014;65(1):41–70. Ethics approval and consent to participate 16. D’Souza S, Backhouse-Smith A, Thompson JMD, Slykerman R, Marlow All experimental procedures have been authorized by the Shaanxi Normal G, Wall C, Murphy R, Ferguson LR, Mitchell EA, Waldie KE. Associations University and written informed consent was obtained from all participants’ between the KIAA0319 dyslexia susceptibility gene variants, antenatal parents. maternal stress, and reading ability in a longitudinal birth cohort. Dys- lexia. 2016;22(4):379–93. Consent for publication 17. Plak RD, Merkelbach I, Kegel CAT, van Ijzendoorn MH, Bus AG. Brief Not applicable. computer interventions enhance emergent academic skills in susceptible children: a gene-by-environment experiment. Learn Instr. 2016;45:1–8. Competing interests 18. Su M, Wang J, Maurer U, Zhang Y, Li J, McBride C, Tardif T, Liu Y, Shu H. The research was conducted in the absence of any commercial or financial Gene–environment interaction on neural mechanisms of orthographic relationships that could be construed as a potential conflict of interest. processing in Chinese children. J Neurolinguistics. 2015;33:172–86. 19. Enge S, Sach M, Reif A, Lesch K-P, Miller R, Fleischhauer M. Cumulative Dopamine Genetic Score predicts behavioral and electrophysiological Received: 24 September 2022 Accepted: 19 May 2023 correlates of response inhibition via interactions with task demand. Cogn Aec ff t Behav Neurosci. 2020;20(1):59–75. 20. Pearson R, Palmer RHC, Brick LA, McGeary JE, Knopik VS, Beevers CG. Addi- tive genetic contribution to symptom dimensions in major depressive disorder. J Abnorm Psychol. 2016;125:495–501. References 21. Steiger H, Thaler L, Gauvin L, Joober R, Labbe A, Israel M, Kucer A. Epistatic 1. Pennington BF. From single to multiple deficit models of developmental interactions involving DRD2, DRD4, and COMT polymorphisms and risk disorders. Cognition. 2006;101(2):385–413. of substance abuse in women with binge-purge eating disturbances. J 2. Shaywitz SE, Shaywitz BA. Dyslexia (specific reading disability). Biol Psy- Psychiatr Res. 2016;77:8–14. chiatry. 2005;57(11):1301–9. Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 12 of 13 22. Walton E, Turner J, Gollub RL, Manoach DS, Yendiki A, Ho B-C, Sponheim 45. Ku Y-M, Anderson RC. Development of morphological awareness in SR, Calhoun VD, Ehrlich S. Cumulative genetic risk and prefrontal activity Chinese and English. Read Writ. 2003;16(5):399–422. in patients with schizophrenia. Schizophr Bull. 2012;39(3):703–11. 46. Pan J, Song S, Su M, McBride C, Liu H, Zhang Y, Li H, Shu H. On the 23. Belsky J, Beaver KM. Cumulative-genetic plasticity, parenting and adoles- relationship between phonological awareness, morphological awareness cent self-regulation. J Child Psychol Psychiatry. 2011;52(5):619–26. and Chinese literacy skills: evidence from an 8-year longitudinal study. 24. Hyde LW, Bogdan R, Hariri AR. Understanding risk for psychopathology Dev Sci. 2016;19(6):982–91. through imaging gene–environment interactions. Trends Cogn Sci. 47. Tighe EL, Schatschneider C. Examining the relationships of component 2011;15(9):417–27. reading skills to reading comprehension in struggling adult readers: a 25. Manuck SB, McCaffery JM. Genetics of stress: gene–stress correlation and meta-analysis. J Learn Disabil. 2016;49(4):395–409. interaction. In: Steptoe A, editor. Handbook of behavioral medicine. New 48. Betjemann RS, Keenan JM, Olson RK, DeFries JC. Choice of reading com- York: Springer; 2010. p. 455–78. prehension test influences the outcomes of genetic analyses. Sci Stud 26. Belsky J, Pluess M. Beyond diathesis stress: differential susceptibility to Read. 2011;15(4):363–82. environmental influences. Psychol Bull. 2009;135:885–908. 49. Gayán J, Olson RK. Genetic and environmental influences on indi- 27. Belsky J, Jonassaint C, Pluess M, Stanton M, Brummett B, Williams R. vidual differences in printed word recognition. J Exp Child Psychol. Vulnerability genes or plasticity genes? Mol Psychiatry. 2009;14(8):746–54. 2003;84(2):97–123. 28. Gottesman Irving I, Gould Todd D. The endophenotype concept 50. Xie Q, Zheng M, Ho CS-H, McBride C, Fong FLW, Wong SWL, Chow BW-Y. in psychiatry: etymology and strategic intentions. Am J Psychiatry. Exploring the genetic and environmental etiologies of phonological 2003;160(4):636–45. awareness, morphological awareness, and vocabulary among chinese- 29. Kendler KS, Neale MC. Endophenotype: a conceptual analysis. Mol Psy- english bilingual children: the moderating role of second language chiatry. 2010;15(8):789–97. instruction. Behav Genet. 2022;52(2):108–22. 30. Flint J, Timpson N, Munafò M. Assessing the utility of intermediate 51. Lim CK-P, Wong AM-B, Ho CS-H, Waye MM-Y. A common haplotype of phenotypes for genetic mapping of psychiatric disease. Trends Neurosci. KIAA0319 contributes to the phonological awareness skill in Chinese 2014;37(12):733–41. children. Behav Brain Funct. 2014;10(1):23. 31. Braff DL. The importance of endophenotypes in schizophrenia research. 52. Venkatesh SK, Siddaiah A, Padakannaya P, Ramachandra NB. Analysis of Schizophr Res. 2015;163(1):1–8. genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in 32. Szatmari P, Maziade M, Zwaigenbaum L, Mérette C, Roy M-A, Joober R, Indian population. J Hum Genet. 2013;58(8):531–8. Palmour R. Informative phenotypes for genetic studies of psychiatric 53. Pan J, Shu H. Rapid automatized naming and its unique contribution to disorders. Am J Med Genet B Neuropsychiatr Genet. 2007;144B(5):581–8. reading: evidence from Chinese dyslexia. In: Chen Xi, Wang Qiuying, Luo 33. Jones MW, Ashby J, Branigan HP. Dyslexia and fluency: parafoveal and Yang Cathy, editors. Reading development and difficulties in monolin- foveal influences on rapid automatized naming. J Exp Psychol Hum gual and bilingual Chinese children. Dordrecht: Springer; 2014. Percept Perform. 2013;39:554–67. 54. Cheng C, Yao Y, Wang Z, Zhao J. Visual attention span and phonologi- 34. Liao C-H, Deng C, Hamilton J, Lee CS-C, Wei W, Georgiou GK. The role cal skills in Chinese developmental dyslexia. Res Dev Disabil. 2021;116: of rapid naming in reading development and dyslexia in Chinese. J Exp 104015. Child Psychol. 2015;130:106–22. 55. Shu H, McBride-Chang C, Wu S, Liu H. Understanding chinese develop- 35. Bowey JA, McGuigan M, Ruschena A. On the association between serial mental dyslexia: morphological awareness as a core cognitive construct. J naming speed for letters and digits and word-reading skill: towards a Educ Psychol. 2006;98:122–33. developmental account. J Res Reading. 2005;28(4):400–22. 56. Li H, Shu H, McBride-Chang C, Liu H, Peng H. Chinese children’s character 36. Pan J, McBride-Chang C, Shu H, Liu H, Zhang Y, Li H. What is in the nam- recognition: visuo-orthographic, phonological processing and morpho- ing? A 5-year longitudinal study of early rapid naming and phonological logical skills. J Res Reading. 2012;35(3):287–307. sensitivity in relation to subsequent reading skills in both native Chinese 57. Song S, Zhang Y, Shu H, Su M, McBride C. Universal and specific predic- and English as a second language. J Educ Psychol. 2011;103:897–908. tors of Chinese children with dyslexia-exploring the cognitive deficits and 37. Savage R, Frederickson N. Evidence of a highly specific relationship subtypes. Front Psychol. 2020;10:2904. between rapid automatic naming of digits and text-reading speed. Brain 58. Doust C, Fontanillas P, Eising E, Gordon SD, Wang Z, Alagöz G, Molz B, Lang. 2005;93(2):152–9. Pourcain BS, Francks C, Marioni RE, et al. Discovery of 42 genome-wide 38. Truong DT, Adams AK, Paniagua S, Frijters JC, Boada R, Hill DE, Lovett significant loci associated with dyslexia. Nat Genet. 2022;54:1621–1629. MW, Mahone EM, Willcutt EG, Wolf M, et al. Multivariate genome-wide 59. Widaman KF, Helm JL, Castro-Schilo L, Pluess M, Stallings MC, Belsky J. association study of rapid automatised naming and rapid alternating Distinguishing ordinal and disordinal interactions. Psychol Methods. stimulus in Hispanic American and African-American youth. J Med Genet. 2012;17:615–22. 2019;56(8):557. 60. Fritz MS, MacKinnon DP. Required sample size to detect the mediated 39. Gialluisi A, Andlauer TFM, Mirza-Schreiber N, Moll K, Becker J, Hoffmann effect. Psychol Sci. 2007;18(3):233–9. P, Ludwig KU, Czamara D, St Pourcain B, Brandler W, et al. Genome-wide 61. Tofighi D, MacKinnon DP. RMediation: an R package for mediation analy- association scan identifies new variants associated with a cognitive sis confidence intervals. Beh Res Meth. 2011;43(3):692–700. predictor of dyslexia. Transl Psychiatry. 2019;9(1):77. 62. Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing 40. Andreola C, Mascheretti S, Belotti R, Ogliari A, Marino C, Battaglia M, and comparing indirect effects in multiple mediator models. Beh Res Scaini S. The heritability of reading and reading-related neurocogni- Meth. 2008;40(3):879–91. tive components: a multi-level meta-analysis. Neurosci Biobehav Rev. 63. Docherty SJ, Kovas Y, Plomin R. Gene-environment interaction in 2021;121:175–200. the etiology of mathematical ability using SNP sets. Behav Genet. 41. Olson RK, Hulslander J, Christopher M, Keenan JM, Wadsworth SJ, Willcutt 2011;41(1):141–54. EG, Pennington BF, DeFries JC. Genetic and environmental influences 64. Sweitzer MM, Halder I, Flory JD, Craig AE, Gianaros PJ, Ferrell RE, Manuck on writing and their relations to language and reading. Ann Dyslexia. SB. Polymorphic variation in the dopamine D4 receptor predicts 2013;63(1):25–43. delay discounting as a function of childhood socioeconomic status: 42. Byrne B, Samuelsson S, Wadsworth S, Hulslander J, Corley R, DeFries JC, evidence for differential susceptibility. Soc Cogn Aec ff t Neurosci. Quain P, Willcutt EG, Olson RK. Longitudinal twin study of early literacy 2012;8(5):499–508. development: Preschool through Grade 1. Read Writ. 2007;20(1):77–102. 65. Pluess M, Belsky J. Vantage sensitivity: Individual differences in response 43. Mascheretti S, Riva V, Feng B, Trezzi V, Andreola C, Giorda R, Villa M, to positive experiences. Psychol Bull. 2013;139:901–16. Dionne G, Gori S, Marino C, et al. The Mediation role of dynamic multi- 66. Si S, Su Y, Zhang S, Zhang J. Genetic susceptibility to parenting style: sensory processing using molecular genetic data in dyslexia. Brain Sci. DRD2 and COMT influence creativity. Neuroimage. 2020;213: 116681. 2020;10(12):993. 44. Kirby JR, Deacon SH, Bowers PN, Izenberg L, Wade-Woolley L, Parrila R. Children’s morphological awareness and reading ability. Read Writ. 2012;25(2):389–410. Zhao et al. Behavioral and Brain Functions (2023) 19:10 Page 13 of 13 67. Norton ES, Wolf M. Rapid Automatized Naming (RAN) and reading fluency: implications for understanding and treatment of reading dis- abilities. Annu Rev Psychol. 2012;63(1):427–52. 68. McBride-Chang C, Lam F, Lam C, Chan B, Fong CYC, Wong TTY, Wong SWL. Early predictors of dyslexia in Chinese children: familial history of dyslexia, language delay, and cognitive profiles. J Child Psychol Psychia- try. 2011;52(2):204–11. 69. Song S, Georgiou GK, Su M, Hua S. How well do phonological awareness and rapid automatized naming correlate with Chinese reading accuracy and fluency? Meta-analysis Sci Stud Read. 2016;20(2):99–123. 70. Georgiou GK, Papadopoulos TC, Fella A, Parrila R. Rapid naming speed components and reading development in a consistent orthography. J Exp Child Psychol. 2012;112(1):1–17. 71. Papadopoulos TC, Spanoudis GC, Georgiou GK. How is RAN related to reading fluency? A comprehensive examination of the prominent theo - retical accounts. Front Psychol. 2016;7:1217. 72. Peng P, Wang C, Tao S, Sun C. The deficit profiles of Chinese children with reading difficulties: a meta-analysis. Educ Psychol Rev. 2017;29(3):513–64. 73. Landerl K, Ramus F, Moll K, Lyytinen H, Leppänen PH, Lohvansuu K, O’Donovan M, Williams J, Bartling J, Bruder J. Predictors of developmental dyslexia in European orthographies with varying complexity. J Child Psychol Psychiatr. 2013;54(6):686–94. 74. Paracchini S, Thomas A, Castro S, Lai C, Paramasivam M, Wang Y, Monaco AP. The chromosome 6p22 haplotype associated with dyslexia reduces the expression of KIAA0319, a novel gene involved in neuronal migration. Human Mol Genet. 2006;15(10):1659–66. 75. Velayos-Baeza A, Toma C, Paracchini S, Monaco AP. The dyslexia-asso- ciated gene KIAA0319 encodes highly N- and O-glycosylated plasma membrane and secreted isoforms. Hum Mol Genet. 2007;17(6):859–71. 76. Londin ER, Meng H, Gruen JR. A transcription map of the 6p22. 3 reading disability locus identifying candidate genes. BMC Genomics. 2003;4(1):1–8. 77. Jamadar S, Powers NR, Meda SA, Gelernter J, Gruen JR, Pearlson GD. Genetic influences of cortical gray matter in language-related regions in healthy controls and schizophrenia. Schizophr Res. 2011;129(2–3):141–8. 78. Nicolson R, Fawcett AJ, Dean P. Dyslexia, development and the cerebel- lum. Trends Neurosci. 2001;24(9):515–6. 79. Li H, Yuan Q, Luo YJ, Tao W. A new perspective for understanding the con- tributions of the cerebellum to reading: the cerebro-cerebellar mapping hypothesis. Neuropsychologia. 2022;170:108231. 80. Wang Z, Zhao S, Zhang L, Yang Q, Cheng C, Ding N, Zhao J. A genome-wide association study identifies a new variant associated with word reading fluency in Chinese children. Genes Brain Behav. 2023;22(1):e12833. 81. Centanni TM, Booker AB, Sloan AM, Chen F, Maher BJ, Carraway RS, Kilgard MP. Knockdown of the dyslexia-associated gene Kiaa0319 impairs temporal responses to speech stimuli in rat primary auditory cortex. Cereb Cortex. 2014;24(7):1753–66. 82. Pinel P, Fauchereau F, Moreno A, Barbot A, Lathrop M, Zelenika D, Dehaene S. Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions. J Neurosci. 2012;32(3):817–25. 83. Ramus F, Rosen S, Dakin SC, Day BL, Castellote JM, White S, Frith U. Theories of developmental dyslexia: insights from a multiple case study of dyslexic adults. Brain. 2003;126(4):841–65. 84. Neef NE, Müller B, Liebig J, Schaadt G, Grigutsch M, Gunter TC, Friederici AD. Dyslexia risk gene relates to representation of sound in the auditory Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : brainstem. Dev Cognit Neurosci. 2017;24:63–71. 85. Mascheretti S, Gori S, Trezzi V, Ruffino M, Facoetti A, Marino C. Visual fast, convenient online submission motion and rapid auditory processing are solid endophenotypes of thorough peer review by experienced researchers in your ﬁeld developmental dyslexia. Genes Brain Behav. 2018;17(1):70–81. 86. McGrath LM, Peterson RL, Pennington BF. The multiple deficit model: rapid publication on acceptance progress, problems, and prospects. Sci Stud Read. 2020;24(1):7–13. support for research data, including large and complex data types 87. Thomas D. 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Behavioral and Brain Functions – Springer Journals
Published: Jun 1, 2023
Keywords: KIAA0319; Reading ability; Rapid automatized naming; Differential susceptibility model; Gene-environment interaction
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