Abstract

1. Sample Collection Sample processing SNP association via Taqman assay (ASPM and HAR1) Sequencing (HAR1) Replication of DCDC2 and KIAA0319 in a single population with language disorder S.K. Iyengar1, J.B. Tomblin2, K.J. Kelsey3, J.B. Bjork3, L.E. Sucheston4, B.K. Samelson3, J.C. Murray3 1) Dept Epid/Biostat, Case Western Reserve Univ, Cleveland, OH; 2) Dept Speech Pathology and Audiology, U of Iowa, Iowa City, IA; 3) Dept Pediatrics, U of Iowa, Iowa City, IA; 4) Dept Biostatistics, SUNY-Buffalo, Buffalo, NY Abstract • DCDC2 and KIAA0319 have been independently associated with reading deficits in separate populations • Language phenotypes and DNA were collected on triads of 581 second-grade children. • Genes were typed using Taqman assays. • Five SNP markers showed significant values for various language measures in DCDC2, and three markers showed significant values for KIAA0319. • DCDC2 and KIAA0319 show evidence of association for speech, language and reading related measures within a single population. Introduction Results • A region (DYX2) on chromosome 6 (6p21) has been linked in several studies to poor reading and reading related phenotypes. These phenotypes often are concerned with word decoding, and the ability to perform cognitive operations on sound properties of words. • Several genes in this region have been considered as candidates for these reading related deficits. Two in particular (DCDC2 and KIAA0319) have been repeatedly associated with reading phenotypes. . • KIAA0319 - Francks et al., 2004 and Cope et al., 2005 reported associations of KIAA0319 to reading related phenotypes but did not find association with DCDC2. Luciano et al. (2007) has also reported an association of reading and spelling to this locus. • DCDC2 - Meng et al., 2005 and Schumacher et al., 2006 reported association of reading related phenotypes to DCDC2 but not to KIAA0319. Meng also reported a strong association with a deletion in Intron 2. • One additional study (Deffenbacher et al. 2004) reported linkage to both genes in the same population. • DCDC2 • Five markers, rs7983845, rs807701, rs1417740, rs793794, and rs813227, showed significant p-values across multiple language measures (see table 2 and figure 1) • No significance was noted for the DCDC2 deletion within intron 2. • KIAA0319 • Three markers, rs12193738, rs5026394, and rs9393572, showed significant p-values across multiple language measures (see table 2 and figure 2) DCDC2 Table 2Significant SNP results with associating language measures KIAA0319 Figure 1 Gene structure, conservation, linkage disequilibrium, and significant single-point SNP results of language associations for the gene DCDC2 Methods Figure 2 Gene structure, conservation, linkage disequilibrium, and significant single-point SNP results of language associations for the gene KIAA0319 Conclusions Participants 581 second grade children who were members of a longitudinal cohort served as participants. The children were sampled from a larger population sample based on their spoken language status in kindergarten. Thirty-seven percent had poor spoken language (<10th percentile on two measures of language) in kindergarten, the remainder had normal language abilities. Phenotyping All children were administered a range of tasks that measured speech, language, reading and intelligence. With the exception of speech sound production ability which was obtained in kindergarten, the measures were obtained in 2nd grade. Table 1 describes these measures. • DCDC2 and KIAA0319, two genes linked to dyslexia in independent populations, show association with reading and other cognitive linguistic measures in the sample population • This study provides a replication of the six previous studies demonstrating association of DCDC2 and/or KIAA0319 and also provides replication of Deffenbacher et al.’s finding of both genes linked or associated to reading related phenotypes in the same sample. • It is hypothesized that these reading-related loci may affect slightly different neurodevelopmental pathways and contribute to different profiles of reading impairment. • DCDC2 • Phenotypes associated with DCDC2 are closely related to phonological abilities and consistent with core features of dyslexia. • Association of reading related phenotypes to the intron 2 deletion (Meng et al. 2005) was not replicated • KIAA0319 • Phenotypes associated with KIAA0319 are more diverse, but include aspects of language associated with meaning and general intellectual function. Table 1 Behavioral phenotypes and specific tests used for phenotypes. Genotyping Saliva, blood, and/or cheek swabs were collected from nuclear families identified via a longitudinal language study. Samples were processed using standard protocols. Samples were typed using Taqman Pre-designed Genotyping Assays under standard reaction conditions. Five single nucleotide polymorphisms (SNPs) were genotyped for ASPM and seven around HAR1. Marker selection was based on haplotype block structure, minor allele frequency, and proximity to conserved regions. A case-control design based on language and reading composite scores was used to sequence 218 individuals at HAR1. Single SNP association was performed via linear regression, accounting for sibling and family effects by ASSOC in the S.A.G.E. software package. Haplotype analyses were performed using the Pedigree Disequilibrium Test (PDT) through Unphased. Acknowledgments Further Information This research was supported by grants DC00496 and DC02746 from the National Institute on Deafness and Other Communicative Disorders. We would also like to thank Katy Mueller, Marlea O’Brien, Rick Arenas, Kathy Frees, Juanita Limas, Marla Johnson, and Adela Mansilla for their work on this project. http://genetics.uiowa.edu http://www.uiowa.edu/~clrc http://www.uiowa.edu