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.

Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review

“…An association between white matter volume in the left temporo‐parietal region and KIAA0319 SNP rs6935076 has been identified (Darki et al, ) and replicated with an additional right hemisphere effect when data from a third longitudinal time point were added to the analysis (Darki et al, ). Furthermore, Eicher et al () reported decreased cortical thickness in a left orbitofrontal region in carriers of the minor allele of the SNP rs9461045 (associated with single‐word reading and spelling ability; Dennis et al, ) relative to those homozygous for the major allele within a sample of individuals ages 3–20 years from the Pediatrics Imaging Neurocognition Genetics study (PING) database . With regard to structural connectivity, the minor allele of the same SNP was associated with reduced white matter integrity in the corpus callosum.…”

“…In addition to DCDC2 and KIAA0319 , two additional genes within 6p22‐21.3 ( THEM2 and NRSN1 ) have been linked with reading ‐ associated neural structure and/or function across multiple studies. Presence of the minor allele at rs3777663 in THEM2 (also known as ACOT13 and previously identified as a protective allele [Eicher et al, ]) has been linked to increased cortical thickness in the left inferior frontal region (Eicher et al, ). In a separate study, Pinel et al () found that THEM2 SNP rs17243157 was associated with functional asymmetry in a posterior temporal region during reading and speech listening tasks, with a stronger effect for reading.…”

“…Two neuroimaging genetic studies of this locus suggest associations with neural structure. Eicher et al () reported suggestive associations between gray matter structure and SNPs in and upstream of GCFC2. A separate study linked one DYX3 SNP to decreased white matter volume in the posterior corpus callosum and cingulum, suggesting a disturbance in interhemispheric connectivity between posterior reading‐related regions (Scerri et al, ).…”

The Relationship between White Matter and Reading Acquisition, Refinement and Maintenance

“…This questionnaire assessed medical, developmental, and behavioral history of participants, in addition to the family history of medication, alcohol problems, and so on. The cognitive assessment was conducted using NIH Toolbox Cognition Battery [32]. This toolbox consisted of tests measuring executive functions, language, and attention (for a complete detailed discussion on all of the collected behavioral measures, see [33]).…”

Whole genome association study of brain‐wide imaging phenotypes: A study of the ping cohort

“…PING DTI imaging techniques, data acquisition, and analyses are discussed briefly below. In-depth descriptions can be found elsewhere (Eicher et al, 2013(Eicher et al, , 2015Fjell et al, 2012).…”