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Association​ ​Of​ ​The​ ​DYX1C1​ ​Gene​ ​With​ ​Chinese Proceedings of the 51st Hawaii International Conference on System Sciences j 2018 Association of the DYX1C1 Gene with Chinese Literacy in a Healthy Chinese ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Population by Latent Class and LASSO Analyses ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Mary Miu Yee Waye Cynthia O. Siu Connie Suk-han Ho ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ COS and Associates Ltd. Dept. of Psychology, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ The Nethersole School of [email protected] The University of Hong Kong ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Nursing, [email protected] ​ ​ Catherine McBride ​ ​ The Chinese University of Dept. of Psychology, Cheuk Wa Wong ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Hong Kong The Chinese University of School of Biomedical Sciences, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Hong Kong The Chinese University of HK ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ [email protected] [email protected] [email protected] ​ ​ Abstract for decades. With the discovery of the first dyslexia candidate gene DYX1C1, it was hoped that this could help us better understand reading difficulties and serve DYX1C1, the first dyslexia candidate gene, has been associated with developmental dyslexia in different as a bridge to enhance reading abilities in the general population [1], [2]. The original report implicating populations, but its influence on reading abilities in the ​ ​ ​ general population is less well known. Copy number DYX1C1 (including SNP rs3743205) in the etiology of variants (CNVs) have been implicated in dyslexia was found in a study of Finnish dyslexia neurodevelopmental and childhood-onset disorders family with a child with dyslexia by breakpoint involving cognitive development in previous studies. In mapping [3], with the gene located in a loci on ​ ​ this report, we investigated the extent to which genomic chromosome 15q21.3 [4]. Another study confirmed that CNVs for the SNP previously linked to dyslexia, -3G/A ​ ​ DYX1C1 influences reading and spelling ability with (rs3743205) in the gene DYX1C1, contribute to Chinese and English literacy in the general population in a additional effects on short-term information storage or Chinese cohort, and whether these processes, in turn, rehearsal, but rs3743205 was not associated with are influenced by environmental factors, such as family dyslexia as reported by Taipale et al; the reason could income, parents’ education, and IQ. Our findings be that this SNP has a very low minor allele frequency suggest that the logR ratio (which is a way to detect in that sample (0.002) [5]. Since then, many more ​ ​ ​ CNVs) of a previously reported dyslexia-related SNP, candidate genes have been reported and there are genes -3G/A (rs3743205) is significantly associated with that seems to be affecting different populations, e.g. Chinese literacy in a cohort of Chinese children with association of DYX1C1 with German [6], Chinese normal reading abilities. ​ ​ ​ ​ ​ ​ [7]–[9], Australian [5], [10], and Swiss children (in the ​ ​ ​ NeuroDys Consortium including children from Austria, 1. Introduction ​ ​ ​ ​​ ​​ ​​ ​​ ​​ France, Germany, The Netherlands, Switzerland, Finland, Hungary, and the United Kingdom [11], while ​ ​ Reading abilities could be affected in children others are not so clearly universal [12]. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​​ ​ with normal intellectual abilities. The reason behind DYX1C1 was shown to be one of the dyslexia developmental dyslexia has perplexed neuroscientists candidate genes that was associated with white matter URI: http://hdl.handle.net/10125/50243 Page 2804 ISBN: 978-0-9981331-1-9 (CC BY-NC-ND 4.0) volume in the left temporoparietal region which affects role of environmental factors in literacy skills has also reading ability [13]. However this gene’s effect on brain been studied previously [21], [22]. ​ ​ ​ ​ ​ ​ ​ ​​ ​ ​ ​ volume is unclear since the knockdown of Dyx1c1 (through RNA interference, RNAi, in rats) did not affect the cortical volume, hippocampal volume, or 2. Materials and Method midsagittal area of the corpus callosum in rats, even ​ ​​ ​​ ​ ​ ​ ​ though knockdown rats has long-term deficits in their 2.1. Participants visual attention abilities, in addition to rapid and ​ ​ complex auditory processing abilities [14]. ​ ​ ​ ​ ​ ​ ​ ​​ ​ The mechanism of DYX1C1 as a dyslexia Informed consent was given to the participant’s parent susceptibility gene was postulated to be due to its role prior to testing. Depending upon the parent’s in neuronal migration mediated by its ciliary function as preference, the children were tested either in a a dynein axonemal assembly factor [15]–[18], as well as laboratory setting, their school, or their home by trained ​ ​ its possible interactions with the U-box protein CHIP experimenters. The test took approximately 2 hours; (carboxy terminus of Hsc70-interacting protein) which five-minute breaks were given every 30 minutes of is involved in the degradation of estrogen receptors testing. A performance report and $720 HKD incentive were given for participation. alpha (ERalpha) and beta (ERbeta). These protein ​ ​ ​ ​ ​ ​ interaction complexes have been demonstrated along the neurites of primary rat hippocampal neurons, and is 2.2. Inclusion Criteria ​ ​​ ​ ​ thought to affect brain development and regulate cognitive functions [19]. Supporting this idea, ​ ​ Ninety-six Hong Kong Chinese-English bilingual neuroimaging results also revealed that there was both a ​ children (Age M=7.6 years, SD=1.17, Grades 1-4; 65 main effect of the gene and a gene × age interaction, females) were included in the analysis. They were possibly not only reflecting the participation of selected from a fellow classmate of pairs of twins in DYX1C1 in early brain development but also in Hong Kong involved in another study: a twin study with pathways that could affect later myelination at both the following criteria: They were not diagnosed as time points of measurement, separated by 2 years [20]. ​ ​ having any special educational needs, including The interaction of DYX1C1 with estrogen receptors developmental dyslexia, hearing or visual impairment, (and thus implicating its role in the sex hormone physical or intellectual disability, speech and language signaling pathway) is also supported by the fact that two impairment, attention deficit/hyperactivity disorder, or of the polymorphisms studied by Darki’s group, autistic spectrum disorders. ​ ​ ​ ​ rs3743204 and rs3743205, are part of a haplotype of three SNPs associated specifically with female dyslexic 2.3. Phenotypes subjects in a sample of 366 German trios [6]. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​​ ​ Although DYX1C1 has been shown to be Cognitive-linguistic and literacy measures, including associated with developmental dyslexia, the role of this non-verbal intelligence, rapid digit naming, gene in reading development in the general population phonological awareness, lexical decision, without dyslexia is not clear. There was a study morphological construction, vocabulary knowledge, showing that in a group 248 children in Beijing, there pure copying, delayed copying, and spelling were given was marginal association of certain SNPs of DYX1C1 to the participants as described previously [22]. For (rs11629841) with children’s orthographic judgements ​ ​ rapid digit naming, the child will be asked to name 8 for children at age 7 and 8 but less so at age 6, and rows of 5 digits given to them rapidly. Two trials were association of this SNP was found with Chinese given and the time averaged. For phonological character dictation at ages 9, 10 and 11 years, but no awareness, children were required to: 1). take away one significant association with other SNPs of DYX1C1 syllable from three-syllable words or pseudowords and they have studied (rs3743205 or rs57809907) [8]. The ​ ​ 2). say a one to three syllable word or pseudoword Page 2805 aloud, but without saying the onset. For lexical interpolation of canonical genotype clusters [23]. R is ​ ​ decision, the children were asked to distinguish real the intensity of dyelabeled molecules that have words from pseudowords. For discourse skills, the hybridized to the beads on the array and with potentially children were asked to arrange the sequence of several different patterns of CNV influences on literacy. For sentences related to a story correctly. For morphological each SNP, raw signal intensity values were measured construction, children were asked to construct new for the A and B alleles and subject to a five-step compounds/words for the presented concepts based on normalization procedure using the signal intensity of all previously acquired morphemes. For vocabulary SNPs (see Illumina white paper at ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ knowledge, children were tested on their receptive https://icom.illumina.com/icom/software.ilmn). This vocabulary, expressive vocabulary and vocabulary procedure produces the X and Y values for each SNP. definitions. For reading comprehension, the children The total signal intensity R = X + Y, where the X and Y were asked to respond to some questions orally after values for each SNP represent the experiment-wide reading 3 passages. For one minute word reading, the normalized signal intensity on the A and B alleles, children were asked to read as many of the 90 words respectively. Composite literacy measures were defined given in one minute. For Chinese word reading, they by combined “word reading” and “dictation” skills in were asked to read as many of the words until they fail Chinese and English languages. ​ ​ ​ ​ ​ ​ 15 words in a row. For English word reading, they were In the LASSO (Least
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