title: Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ.
abstract: Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI-and their associated deficits-are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.
authors: Department of Genetics, Yale University School of Medicine, New Haven, CT, USA, john.eicher@yale.edu.
authors: John D
authors: JD
authors: Eicher
authors: Natalie R
authors: NR
authors: Powers
authors: Laura L
authors: LL
authors: Miller
authors: Kathryn L
authors: KL
authors: Mueller
authors: Sara
authors: S
authors: Mascheretti
authors: Cecilia
authors: C
authors: Marino
authors: Erik G
authors: EG
authors: Willcutt
authors: John C
authors: JC
authors: DeFries
authors: Richard K
authors: RK
authors: Olson
authors: Shelley D
authors: SD
authors: Smith
authors: Bruce F
authors: BF
authors: Pennington
authors: J Bruce
authors: JB
authors: Tomblin
authors: Susan M
authors: SM
authors: Ring
authors: Jeffrey R
authors: JR
authors: Gruen
mesh_terms: D015815:Cell Adhesion Molecules; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D003120:Colorado; D004268:DNA-Binding Proteins; D004410:Dyslexia / Q000235:genetics*; D056426:Genetic Loci; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007361:Intelligence Tests; D007484:Iowa; D007558:Italy; D007806:Language Disorders / Q000235:genetics*; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases; D011506:Proteins / Q000235:genetics; D011544:Pseudogenes; D011581:Psychological Tests; D011932:Reading; D013869:Thiolester Hydrolases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C510451:DCDC2 protein, human; D004268:DNA-Binding Proteins; C500377:KIAA0319 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011506:Proteins; C104952:RIPOR2 protein, human; D014157:Transcription Factors; C514740:ACOT13 protein, human; D013869:Thiolester Hydrolases; D010727:Phosphoric Diester Hydrolases; C474866:TDP2 protein, human