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Characterization of the DYX2 locus on chromosome 6p22 with reading disability,language impairment,and IQ |
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| Authors: | John D Eicher Natalie R Powers Laura L Miller Kathryn L Mueller Sara Mascheretti Cecilia Marino Erik G Willcutt John C DeFries Richard K Olson Shelley D Smith Bruce F Pennington J Bruce Tomblin Susan M Ring Jeffrey R Gruen |
| Institution: | 1. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 2. Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA 3. MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK 4. Hearing, Language and Literacy, Murdoch Childrens Institute, Melbourne, Australia 5. Department of Communication Sciences and Disorders, The University of Iowa, Iowa City, IA, USA 6. Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy 7. Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec, Québec, Canada 8. Department of Psychiatry and Neuroscience, Université Laval, Québec, Canada 10. Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA 9. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA 11. Departments of Pediatrics and Developmental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA 12. Department of Psychology, University of Denver, Denver, CO, USA 13. Investigative Medicine Program, Yale Child Health Research Center, Yale University School of Medicine, New Haven, CT, USA |
| 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. |
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