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A Family-Based Association Study Does Not Support DYX1C1 on 15Q21.3 As a Candidate Gene in Developmental Dyslexia

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A Family-Based Association Study Does Not Support DYX1C1 on 15Q21.3 As a Candidate Gene in Developmental Dyslexia European Journal of Human Genetics (2005) 13, 491–499 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00 www.nature.com/ejhg ARTICLE A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia Cecilia Marino*,1, Roberto Giorda2, Maria Luisa Lorusso3, Laura Vanzin1, Nello Salandi1, Maria Nobile1, Alessandra Citterio1, Silvana Beri2, Valentina Crespi1, Marco Battaglia4,5 and Massimo Molteni1 1Department of Child Psychiatry, Scientific Institute ‘Eugenio Medea’, via Don L Monza 20, 23842 Bosisio Parini (LC), Italy; 2Molecular Biology Laboratory, Scientific Institute ‘Eugenio Medea’, via Don L Monza 20, 23842 Bosisio Parini (LC), Italy; 3Department of Neuropsychology, Scientific Institute ‘Eugenio Medea’, via Don L Monza 20, 23842 Bosisio Parini (LC), Italy; 4Department of Psychology, Vita-Salute San Raffaele University at IRCCS ‘San Raffaele’, via Stamira d’Ancona 20, Milan, Italy; 5Division of Epidemiology, National Institutes of Public Health, P.O. Box 4404 Nydalen, Oslo, Norway We applied a family-based association approach to investigate the role of the DYX1C1 gene on chromosome 15q as a candidate gene for developmental dyslexia (DD) to 158 families containing at least one dyslexic child. We directly sequenced exons 2 and 10 of the DYX1C1 gene and found eight single nucleotide polymorphism (SNPs), three of which (À3G4A, 1249 G4T, 1259 C4G) were suitable for the genetic analyses. We performed single- and multimarker association analyses with DD as a categorical trait by FBAT version 1.4 and TRANSMIT version 2.5.4 programs. Our sample had a power of at least 80% to detect an association between the selected phenotypes and the informative polymorphisms at a significance level of 5%. The results of the categorical analyses did not support the involvement of the DYX1C1 gene variants in this sample of dyslexics and their relatives. Quantitative and multimarker analyses, which provide greater power to detect loci with a minor effect, consistently yielded nonsignificant results. While D1X1C1 is a good candidate gene for DD, we were unable to replicate the original findings between DYX1C1 gene and DD, perhaps due to genetic heterogeneity. European Journal of Human Genetics (2005) 13, 491–499. doi:10.1038/sj.ejhg.5201356 Published online 26 January 2005 Keywords: developmental dyslexia; DYX1C1; quantitative analysis; family-based association study Introduction reading difficulties are the hint that most often leads to a Developmental dyslexia (DD) is a heritable1 complex clinical diagnosis of DD, they probably constitute only the disorder, which usually becomes apparent in the first most visible dysfunction of a more composite picture of a school years as soon as children learn to read. While defective neurocognitive profile, which is likely to predate the diagnosis and extend across different functions.2,3 As such, DD could be better conceptualized as a complex *Correspondence: Dr C Marino, Department of Child Psychiatry, Scientific syndrome, whose exact etiopathogenetic pathways from Institute ‘Eugenio Medea’, via Don L Monza 20, 23842 Bosisio Parini (LC), genes to phenotype are still unknown in spite of consider- Italy. Tel: þ 39 031 877 595; Fax: þ 39 031 877 356; able effort.4 Genetic studies have helped to unravel part of E-mail: [email protected] Received 17 July 2004; revised 8 November 2004; accepted 11 November this etiologic dilemma, however. The linkage approach that 2004 can be applied without any a priori hypothesis on the Family-based association study of DD C Marino et al 492 etiopathogenetic nature of the disorder has revealed referred mainly by paediatricians and teachers from several candidate chromosomal areas on chromosomes schools of the same geographical area for diagnosis and 1,5,6 2,7–9 3,10 6p,11 – 18 6q,19 15q,13,20 – 26 and 18.27 treatment of a wide range of mental disorders, including Recently, DYX1C1 has been proposed as a candidate gene learning disorders and dyslexia.26,30 Probands were re- in the 15q region in a family cosegregating a cruited in our sample if they met criteria for DD based on t(2;15)(q11;q21) and DD;28 DYX1C1 contains 10 exons the Diagnostic and Statistical Manual of Mental Disorders, spanning about 78 kb of genomic DNA and codes for a Fourth Edition (DSM IV);31 accordingly, exclusion criteria nuclear tetratricopeptide repeat domain protein. Eight were the presence of neurological or sensoneural disorders. SNPs were identified by direct sequencing, five of which Reading abilities were investigated through a battery of were in the coding region (4C4T, 270G4A, 572G4A, tests that encompassed several reading tasks standardized 1249G4T, 1259C4G), whereas three resided in the 50 on the Italian population32,33 and the Wechsler Intelli- untranslated region (À164C4T, À3G4A, À2G4A). DD gence Scale for Children, Revised.34 was associated with alleles À3A and 1249T in a case– Reading tests were as follows: control sample (corrected P-values 0.016 and 0.048 (1) Text Reading: ‘Prove di rapidita` e correttezza nella respectively). Furthermore, the À3A/1249T haplotype lettura del gruppo MT’ (‘Test for speed and accuracy in showed association with DD in the case–control sample reading, developed by the MT group’), a text-reading task (P ¼ 0.015) and in nine informative trios (P ¼ 0.025).28 that assesses reading abilities for meaningful material. It Support for DYX1C1 as contributing to DD was recently provides separate scores for speed (seconds) and accuracy found in a sample of 148 families identified through a (expressed in number of errors). Texts increase in complex- proband with reading difficulties:29 evidence for linkage ity with grade level. Norms are provided for each text.33 disequilibrium with DD was found for the rs11629841 (2) Single word and nonword reading subtests of ‘Batteria per polymorphism in intron 4 and haplotypes of this poly- la Valutazione della Dislessia e Disortografia Evolutiva’ morphism. However, quantitative analyses of reading and (Battery for the assessment of Developmental Reading and reading-related phenotypes were significant for the À3G Spelling Disorders), Subtests 4 and 5 respectively.32 These allele, which contrasts with the original finding of Taipale tests assess speed (s) and accuracy (expressed in number of et al28 association with the alternative allele (À3A) of this errors) in reading word lists (four lists of 24 words) and polymorphism. Moreover, a linkage disequilibrium was nonword lists (three lists of 16 nonwords) and provide found29 between DD and the haplotype À3G/1249G, grade norms from the second to the last grade of junior instead of the association with the more rare À3A/1249T high school. haplotype originally reported by Taipale et al.28 Subjects’ scores in each of these tasks are expressed in In this study we assessed the possible association with standard deviation units relative to the norm for the age- DD and six of the SNPs previously identified within appropriate general Italian population. DYX1C1,28 namely À164C4T, À3G4A, À2G4A, 4C4T, The information gathered in the assessments described located in exon 2, and 1249G4T and 1259C4G, in exon above is employed to decide whether each children would 10, in order to further investigate the contribution of this meet the following standardized inclusion criteria: gene to DD. We focused on exons 2 and 10 because they (A) Performance on timed text-reading tests at least 2 contain most of the known polymorphisms, including the standard deviations below the general population mean on two that showed association with DD in the original at least one of the following two parameters: (1) accuracy report.28 We adopted the intrafamily design in order to (2) speed; Or: overcome spurious associations due to population stratifi- (B) A text reading score at least 1.5 standard deviations cation effects. We implemented both single and multi- below the general population mean on at least one of the marker analyses of DD as a categorical trait. Since DD is previous parameters, and an absolute score at least 2 likely to involve several different neurocognitive functions standard deviations below the general population mean upon which subjects differ one from the other quantita- on accuracy or speed in reading single unrelated words or tively,1 we also ran single and multimarker quantitative pronounceable nonwords; analyses with neuropsychological components of the And: phenotypic dyslexic profile. (C) IQ Z85. A total of 158 probands identified as having DD and their biological parents accepted to participate in the study over Methods a period of 37 months. Parents were also asked to allow the Sample participation into the extensive clinical assessment of the This study is based on a sample of children recruited for probands’ siblings (aged between 6 and 18 years) with a reading difficulties from the Department of Child Psychia- history of reading difficulties/probable dyslexia. Only try and Rehabilitation Centre at the Eugenio Medea siblings who met the above-mentioned criteria were Institute, Bosisio Parini, Italy, a facility where children are included in the study. Blood or mouthwash samples were European Journal of Human Genetics Family-based association study of DD C Marino et al 493 then collected from parents, probands and siblings to Raw scores were converted into age-adjusted standard perform genetic analyses. The sample consisted in 133 deviation units from the norm by application of the triads, 12 parent-child pairs and 13 nuclear families with standard norms in the test protocol. two affected offsprings (for a total fo 158 nuclear families It should be noted that, because of transparent ortho- with 171 affected children). Probands mean age was graphy, Italian words can generally be read both via the 10.972.5 (min 7, max 18) and the male to female sex indirect phonological route and/or via the direct lexical ratio was 3.5:1. Siblings were included in all analyses.
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