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Dyslexia Risk Variant Rs600753 Is Linked with Dyslexia-Specific Differential Allelic Expression of DYX1C1

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Dyslexia Risk Variant Rs600753 Is Linked with Dyslexia-Specific Differential Allelic Expression of DYX1C1 Genetics and Molecular Biology, 41, 1, 41-49 (2018) Copyright © 2018, Sociedade Brasileira de Genética. Printed in Brazil DOI: http://dx.doi.org/10.1590/1678-4685-GMB-2017-0165 Research Article Dyslexia risk variant rs600753 is linked with dyslexia-specific differential allelic expression of DYX1C1 Bent Müller1*, Johannes Boltze2,3*, Ivonne Czepezauer1, Volker Hesse4,5, LEGASCREEN Consortium, Arndt Wilcke1* and Holger Kirsten1,6,7* 1Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany. 2Fraunhofer Research Institution for Marine Biotechnology, Department of Medical Cell Technology, Lübeck, Germany. 3Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany. 4German Center for Growth, Development and Health Encouragement in Childhood and Adolescence, Berlin, Germany. 5Charité-University Medicine Berlin, Institute for Experimental Paediatric Endocrinolgy, Berlin, 6Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 7LIFE - Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany. Abstract An increasing number of genetic variants involved in dyslexia development were discovered during the last years, yet little is known about the molecular functional mechanisms of these SNPs. In this study we investigated whether dyslexia candidate SNPs have a direct, disease-specific effect on local expression levels of the assumed target gene by using a differential allelic expression assay. In total, 12 SNPs previously associated with dyslexia and related phe- notypes were suitable for analysis. Transcripts corresponding to four SNPs were sufficiently expressed in 28 cell lines originating from controls and a family affected by dyslexia. We observed a significant effect of rs600753 on ex- pression levels of DYX1C1 in forward and reverse sequencing approaches. The expression level of the rs600753 risk allele was increased in the respective seven cell lines from members of the dyslexia family which might be due to a disturbed transcription factor binding sites. When considering our results in the context of neuroanatomical dys- lexia-specific findings, we speculate that this mechanism may be part of the pathomechanisms underlying the dys- lexia-specific brain phenotype. Our results suggest that allele-specific DYX1C1 expression levels depend on genetic variants of rs600753 and contribute to dyslexia. However, these results are preliminary and need replication. Keywords: dyslexia, SNP, eQTL, differential allelic expression. Received: May 31, 2017; Accepted: August 28, 2017. Introduction ture (Darki et al., 2012). In contrast to relatively well- Dyslexia is a highly heritable disorder. The genetic established knowledge on the gene level, information re- component contributes by up to 60% to this disorder garding the molecular mechanisms of dyslexia candidate (Schulte-Körne, 2010) and several genes are suggested to single nucleotide polymorphisms (SNPs) is still fragmen- affect the development of dyslexia (see Tables S1 and S2). tary. Variants of well-validated genes such as DCDC2 (Dou- The molecular mechanism exerted by a certain SNP blecortin Domain Containing 2), KIAA0319, ROBO1 can be of different nature. On the one hand, SNPs might af- (Roundabout Guidance Receptor 1) and DYX1C1 (Dys- fect the structure of a gene-derived protein. For dyslexia, lexia Susceptibility 1 Candidate 1) are believed to be however, only very few nonsynonymous SNPs affecting involved in disturbed neuronal migration and axonal guid- protein structure and function are known (see Table S2 for ance (Carrion-Castillo et al., 2013) as well as differences of an overview). On the other hand, SNPs might influence the brain phenotypes such as alterations in white matter struc- protein quantitatively, e.g., by altering gene expression lev- els, a phenomenon also referred to as expression quantita- tive loci (eQTL). eQTLs are commonly differentiated in Send correspondence to Bent Müller. Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany. cis-, as well as in trans-acting eQTLs. Trans eQTLs are lo- E-mail: [email protected]. cated distant to the gene which expression is affected and *These authors contributed equally to this work cis eQTLs are located close to the affected gene. 42 Müller et al. Only few studies specifically analyzed the impact of Sanger sequencing of reverse transcribed cDNA. Results dyslexia candidate SNPs on gene expression levels. Two were compared with publically available (dyslexia-uns- groups (Tapia-Páez et al., 2008; Tammimies et al., 2012) pecific) eQTL-data. reported a putative effect of rs3743205 on expression level of DYX1C1. Tammimies et al. (2012) observed that a CpG Materials and Methods site results from the G-allele of this SNP. This might lead to methylation of a transcription factor binding site, and, con- SNP selection, cell lines and characterization steps sequently, in disturbed binding of transcription factors. For the identification of dyslexia candidate SNPs, we Paracchini et al. (2006) observed reduced expression levels conducted a systematic screening using ‘PubMED’ and of KIAA0319 in carriers of the risk haplotype rs4504469- ‘Google Scholar’ for genetic candidate-studies related to rs2038137-rs2143340. In a second study, Dennis et al. dyslexia. The identified SNPs had to map to an exonic, (2009) tested seven SNPs of the KIAA0319 promotor re- 5’-UTR or 3’-UTR location to have the potential to affect gion and observed reduced KIAA01319 expression levels local expression levels of the target genes. For each of these for the minor allele rs9461045-T. However, these experi- SNPs, a minimum of four heterozygous cell lines per group ments were all carried out in cells derived from donors was required to maintain validity of our analyses (Serre et without dyslexia background. Such approaches might miss al., 2008), and the general (non-allele specific) expression effects resulting from a disease-specific genetic back- of the SNP-corresponding transcripts was tested with ground. Previous results from dyslexia, but also from other cDNA-specific primers in the sample cells of interest. complex diseases, motivate to analyze such effects. For ex- In total, 28 Epstein-Barr virus (EBV) immortalized ample, Hannula-Jouppi et al. (2005) observed disease- cell lines derived from B-cells were available. Ten cell lines specific gene-expression levels in dyslexia and Furney et were derived from a three generational German family, in al. (2011) identified an Alzheimer-specific effect for a SNP which dyslexia segregation suggests a full-penetrance, within ZNF292 on entorhinal cortical volume. A disease- autosomal dominant inheritance. A genome-wide linkage specific molecular mechanisms can be understood as an ef- analysis revealed a haplotype of chromosome 12 co-segre- fect which only emerges in affected individuals. This might gating with language impairment (Addis et al., 2010). For a be due to different regulatory networks present in the af- detailed description of the family see Addis et al. (2010). 18 fected individuals. Consequently, certain molecular factor cell lines that served as controls were derived from several might be active in the affected individuals, only, e.g., cer- families with more details available elsewhere (Burkhardt tain transcription factors. If a certain SNP would alter the et al., 2012). genomic binding site of such a disease specific factor, the Extraction of genomic DNA (DNeasy Blood & Tis- effect of this SNP would be also disease-specific, i.e., ob- sue Kit, Qiagen, Hilden, Germany) and subsequent geno- served only in the affected individuals (de la Fuente, 2010). typing was performed by the matrix-assisted laser desor- Another problem that may affect detection of an ef- ption/ionization time-of-flight spectrometry system iPLEX fect of a genetic variant on gene expression might result (Agena, Hamburg, Germany). SNPs had to fulfill Hardy- from general heterogeneity across samples from a variety Weinberg-Equilibrium criteria (HWE; p > 0.05 after Bon- of biological and technical sources, what can decrease ferroni correction), and to exhibit a SNP-wise call rate > study power. However, these limitations can be addressed 97%, as well as a minor allele frequency (MAF) > 0.05. by the direct measurement of cis-regulated allelic expres- SNPs had to be heterozygous in at least four individ- sion differences by differential allelic expression (DAE) ual cell lines to be eligible for analysis. Six SNPs fulfilled (Serre et al., 2008). In this approach, expression differences this criterion and were considered for further analyses. Ap- resulting from the two different alleles of a SNP are ana- propriate cDNA-specific primers were designed and tested lyzed within heterozygous individuals. Consequently, this for blood-specific expression. Gel electrophoresis demon- method is rather robust to biological or technical batch ef- strated sufficient expression of four SNPs in B-cells and fects among individuals. were therefore analyzed for DAE. Figure 1 illustrates the In our study we conducted a stepwise approach to workflow. identify dyslexia-specific effects of SNPs on gene expres- Heterozygous samples were quantified on cDNA and sion. We started with the identification of suitable dyslexia gDNA level. cDNA was reverse-transcribed from RNA us- candidate SNPs having a potential effect on local gene ex- ing Direct-zol RNA MiniPrep (Zymo Research, Irvine, CA, pression
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