title: Dyslexia and language impairment associated genetic markers influence cortical thickness and white matter in typically developing children.
abstract: Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, 06520, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Eicher
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Montgomery
authors.affiliation: Center for Human Development, University of California, La Jolla, San Diego, CA, 92037, USA.|Department of Psychiatry, University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Akshoomoff
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of California, Davis, CA, 95817, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Amaral
authors.affiliation: Scripps Genomic Medicine, Scripps Health, Scripps Translational Science Institute, La Jolla, CA, 92037, USA.
authors.forename: Cinnamon S
authors.initials: CS
authors.lastname: Bloss
authors.affiliation: Scripps Genomic Medicine, Scripps Health, Scripps Translational Science Institute, La Jolla, CA, 92037, USA.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Libiger
authors.affiliation: Scripps Genomic Medicine, Scripps Health, Scripps Translational Science Institute, La Jolla, CA, 92037, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: Scripps Genomic Medicine, Scripps Health, Scripps Translational Science Institute, La Jolla, CA, 92037, USA.
authors.forename: Burcu F
authors.initials: BF
authors.lastname: Darst
authors.affiliation: Sackler Institute for Developmental Psychobiology, Weil Cornell Medical College, New York, NY, 10065, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Casey
authors.affiliation: Department of Medicine, Queen's Medical Center, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.affiliation: Department of Medicine, Queen's Medical Center, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical School, Boston, MA, 01655, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Frazier
authors.affiliation: Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, 21205, USA.|Department of Neurology, Harvard Medical School, Children's Hospital Boston, Boston, MA, 02115, USA.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
authors.affiliation: Department of Medicine, Queen's Medical Center, University of Hawaii, Honolulu, HI, 96813, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Keating
authors.affiliation: Department of Neurology and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, 02129, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Kenet
authors.affiliation: Department of Psychiatry, University of Massachusetts Medical School, Boston, MA, 01655, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kennedy
authors.affiliation: Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, 21205, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Mostofsky
authors.affiliation: Scripps Genomic Medicine, Scripps Health, Scripps Translational Science Institute, La Jolla, CA, 92037, USA.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Murray
authors.affiliation: Department of Pediatrics, University of Southern California, Los Angeles, CA, 90027, USA.|Developmental Cognitive Neuroimaging Laboratory Children's Hospital, Los Angeles, CA, 90027, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sowell
authors.affiliation: Multimodal Imaging Laboratory, University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Hauke
authors.initials: H
authors.lastname: Bartsch
authors.affiliation: Multimodal Imaging Laboratory, University of California, La Jolla, San Diego, CA, 92037, USA.|Department of Neurosciences, University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Kuperman
authors.affiliation: Center for Human Development, University of California, La Jolla, San Diego, CA, 92037, USA.|Multimodal Imaging Laboratory, University of California, La Jolla, San Diego, CA, 92037, USA.|Department of Neurosciences, University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Brown
authors.affiliation: Multimodal Imaging Laboratory, University of California, La Jolla, San Diego, CA, 92037, USA.|Radiology University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Hagler
authors.affiliation: Department of Psychiatry, University of California, La Jolla, San Diego, CA, 92037, USA.|Multimodal Imaging Laboratory, University of California, La Jolla, San Diego, CA, 92037, USA.|Department of Neurosciences, University of California, La Jolla, San Diego, CA, 92037, USA.|Radiology University of California, La Jolla, San Diego, CA, 92037, USA.|Cognitive Science University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Dale
authors.affiliation: Center for Human Development, University of California, La Jolla, San Diego, CA, 92037, USA.|Department of Psychiatry, University of California, La Jolla, San Diego, CA, 92037, USA.|Radiology University of California, La Jolla, San Diego, CA, 92037, USA.|Cognitive Science University of California, La Jolla, San Diego, CA, 92037, USA.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Jernigan
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, 06520, USA. jeffrey.gruen@yale.edu.|Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA. jeffrey.gruen@yale.edu.|Department of Investigative, School of Medicine, Medicine Yale University, New Haven, CT, 06520, USA. jeffrey.gruen@yale.edu.|Department of Pediatrics, Genetics, and Investigative Medicine, Yale Child Health Research Center, 464 Congress Avenue, New Haven, CT, 06520-8081, USA. jeffrey.gruen@yale.edu.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gruen
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D015815:Cell Adhesion Molecules; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D038524:Diffusion Magnetic Resonance Imaging; D056324:Diffusion Tensor Imaging; D004410:Dyslexia / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D007805:Language Development Disorders / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009929:Organ Size; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D013869:Thiolester Hydrolases / Q000235:genetics; D066127:White Matter / Q000000981:diagnostic imaging / Q000254:growth & development / Q000473:pathology; D055815:Young Adult
chemical_list: D015815:Cell Adhesion Molecules; C500377:KIAA0319 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; C104952:RIPOR2 protein, human; C514740:ACOT13 protein, human; D013869:Thiolester Hydrolases
keywords: DYX2; DYX3; Dyslexia; Imaging-genetics; KIAA0319; Language impairment