Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ

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

doi:10.1007/s00439-014-1427-3

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Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ

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Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ

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, …

Human genetics, Vol.133(7), pp.869-881

2014

DOI: 10.1007/s00439-014-1427-3

PMCID: PMC4053598

PMID: 24509779

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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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Title: Subtitle: Characterization of the DYX2 locus on chromosome 6p22 with reading disability, language impairment, and IQ
Creators: John D Eicher - Department of Genetics, Yale University School of Medicine, New Haven, CT USA
Natalie R Powers - Department of Genetics, Yale University School of Medicine, New Haven, CT USA
Laura L Miller - MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
Kathryn L Mueller - Hearing, Language and Literacy, Murdoch Childrens Institute, Melbourne, Australia
Sara Mascheretti - Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco Italy
Cecilia Marino - Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco Italy
Erik G Willcutt - Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA
John C DeFries - Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA
Richard K Olson - Institute for Behavioral Genetics, University of Colorado, Boulder, CO USA
Shelley D Smith - Departments of Pediatrics and Developmental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA
Bruce F Pennington - Department of Psychology, University of Denver, Denver, CO USA
J. Bruce Tomblin - Department of Communication Sciences and Disorders, The University of Iowa, Iowa City, IA USA
Susan M Ring - MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK
Jeffrey R Gruen - Department of Genetics, Yale University School of Medicine, New Haven, CT USA
Resource Type: Journal article
Publication Details: Human genetics, Vol.133(7), pp.869-881
DOI: 10.1007/s00439-014-1427-3
PMID: 24509779
PMCID: PMC4053598
NLM abbreviation: Hum Genet
ISSN: 0340-6717
eISSN: 1432-1203
Publisher: Springer Berlin Heidelberg; Berlin/Heidelberg
Language: English
Date published: 2014
Academic Unit: Communication Sciences and Disorders; Iowa Neuroscience Institute
Record Identifier: 9984070275102771

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