Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a non-parametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Using multimodal neuroimaging in humans, we demonstrate specific interactions between prefrontal activity and midbrain dopaminergic synthesis. A common V(108/158)M substitution in the gene for catecholamine-O-methyltransferase (COMT), an important enzyme regulating prefrontal dopamine turnover, predicted reduced dopamine synthesis in midbrain and qualitatively affected the interaction with prefrontal cortex. These data implicate a dopaminergic tuning mechanism in prefrontal cortex and suggest a systems-level mechanism for cognitive and neuropsychiatric associations with COMT. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are broadly expressed in the developing and adult mammalian brain. BDNF/TrkB-stimulated intracellular signaling is critical for neuronal survival, morphogenesis, and plasticity. It is well known that binding of BDNF to TrkB elicits various intracellular signaling pathways, including mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK), phospholipase Cg (PLCg), and phosphoinositide 3-kinase (PI3K) pathways, and that BDNF exerts biological effects on neurons via activation of similar mechanisms. In addition to TrkB, a low-affinity receptor p75 is also involved in neuronal survival and plasticity. BDNF affects neurons positively or negatively through various intracellular signaling pathways triggered by activation of TrkB or p75. From a clinical standpoint, roles of BDNF have been implicated in the pathophysiology of various brain diseases. The stress-induced steroid hormone, glucocorticoid, and BDNF are putatively associated with the pathophysiology of depression. Recent reports, including our studies, demonstrate possible crosstalk between glucocorticoid- and BDNF/TrkB-mediated signaling. Here, we present a broad overview of the current knowledge concerning BDNF action and associated intracellular signaling as it relates to neuronal protection, synaptic function, and morphological change. Furthermore, understanding the secretion and intracellular dynamics of BDNF proteins is critical as the fate of secreted BDNF may contribute to differences in neuronal response. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Independent studies have shown that candidate genes for dyslexia and specific language impairment (SLI) impact upon reading/language-specific traits in the general population. To further explore the effect of disorder-associated genes on cognitive functions, we investigated whether they play a role in broader cognitive traits. We tested a panel of dyslexia and SLI genetic risk factors for association with two measures of general cognitive abilities, or IQ, (verbal and non-verbal) in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N>5,000). Only the MRPL19/C2ORF3 locus showed statistically significant association (minimum P = 0.00009) which was further supported by independent replications following analysis in four other cohorts. In addition, a fifth independent sample showed association between the MRPL19/C2ORF3 locus and white matter structure in the posterior part of the corpus callosum and cingulum, connecting large parts of the cortex in the parietal, occipital and temporal lobes. These findings suggest that this locus, originally identified as being associated with dyslexia, is likely to harbour genetic variants associated with general cognitive abilities by influencing white matter structure in localised neuronal regions. <s> BIB005 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> In both children and adults there is large variability in reading skill, with approximately 5–10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher-order cognition, is associated with reading and reading-related skills, both at the level of brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill. <s> BIB006 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Abstract Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia. <s> BIB007 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> 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. <s> BIB008 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Abstract Neuroimaging measures provide useful endophenotypes for tracing genetic effects on reading and language. A recent Genome-Wide Association Scan Meta-Analysis (GWASMA) of reading and language skills (N = 1862) identified strongest associations with the genes CCDC136 / FLNC and RBFOX2 . Here, we follow up the top findings from this GWASMA, through neuroimaging genetics in an independent sample of 1275 healthy adults. To minimize multiple-testing, we used a multivariate approach, focusing on cortical regions consistently implicated in prior literature on developmental dyslexia and language impairment. Specifically, we investigated grey matter surface area and thickness of five regions selected a priori : middle temporal gyrus (MTG); pars opercularis and pars triangularis in the inferior frontal gyrus (IFG-PO and IFG-PT); postcentral parietal gyrus (PPG) and superior temporal gyrus (STG). First, we analysed the top associated polymorphisms from the reading/language GWASMA: rs59197085 ( CCDC136 / FLNC ) and rs5995177 ( RBFOX2 ). There was significant multivariate association of rs5995177 with cortical thickness, driven by effects on left PPG, right MTG, right IFG (both PO and PT), and STG bilaterally. The minor allele, previously associated with reduced reading-language performance, showed negative effects on grey matter thickness. Next, we performed exploratory gene-wide analysis of CCDC136 / FLNC and RBFOX2 ; no other associations surpassed significance thresholds. RBFOX2 encodes an important neuronal regulator of alternative splicing. Thus, the prior reported association of rs5995177 with reading/language performance could potentially be mediated by reduced thickness in associated cortical regions. In future, this hypothesis could be tested using sufficiently large samples containing both neuroimaging data and quantitative reading/language scores from the same individuals. <s> BIB009 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | ADDITIONAL GENES LINKED TO READING AND LANGUAGE <s> Abstract Epidemiological population studies highlight the presence of substantial individual variability in reading skill, with approximately 5–10% of individuals characterized as having specific reading disability (SRD). Despite reported substantial heritability, typical for a complex trait, the specifics of the connections between reading and the genome are not understood. Recently, the SETBP1 gene has been implicated in several complex neurodevelopmental syndromes and disorders that impact language. Here, we examined the relationship between common polymorphisms in this gene, reading, and reading associated behaviors using data from an ongoing project on the genetic basis of SRD (n = 135). In addition, an exploratory analysis was conducted to examine the relationship between SETBP1 and brain activation using functional magnetic resonance imaging (fMRI; n = 73). Gene-based analyses revealed a significant association between SETBP1 and phonological working memory, with rs7230525 as the strongest associated single nucleotide polymorphism (SNP). fMRI analysis revealed that the rs7230525-T allele is associated with functional neural activation during reading and listening to words and pseudowords in the right inferior parietal lobule (IPL). These findings suggest that common genetic variation within SETBP1 is associated with reading behavior and reading-related brain activation patterns in the general population. <s> BIB010
Neuroimaging genetic research provides an informative approach to understanding the contributions of novel candidate genes for SRD and DLD and language/reading-related polymorphisms located in intergenic regions. BIB009 reported promising findings in several recently identified candidate genes for reading and language disorders. The minor allele of RBFOX2 SNP rs5995177, previously linked to reading/language skills (Gialluisi et al., 2014) , was significantly associated with decreased cortical thickness in parietal, temporal, and inferior frontal regions of interest BIB009 . Furthermore, three SNPs located upstream of CCDC136 (rs56184882, rs339054, and rs339046) were nominally related to cortical surface area of the inferior frontal gyrus bilaterally BIB009 . Evidence for the role of a set of SNPs located in a noncoding region has also been revealed by neurogenetic methods. Variation on a haplotype formed by rs4234898 and rs11100040 in a noncoding region in chromosome 4q32.1 has been associated with the MMN response in children with SRD BIB004 . Both SNPs were associated with regulation of the glucose transport gene SLC2A3, leading the authors to propose that the attenuated MMN response observed in children with SRD may arise from reduced glucose resulting from the modulation of SLC2A3 expression by rs4234898 and rs11100040. In another investigation, BIB007 reported reduced functional and structural connectivity among left hemisphere reading/language regions in children carrying the risk-allele at rs11100040. Additional research will be needed to investigate a potential causal mechanism among these SNPs, regulation of SLC2A3, connectivity, and reading and language abilities. Several studies have linked the DYX3 genetic locus on chromosome 2 containing GCFC2/C2Orf3 and MRPL19 to SRD   BIB001 , but the role of these genes in neural function remains unknown. Two neuroimaging genetic studies of this locus suggest associations with neural structure. BIB008 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 BIB005 . Scerri and colleagues also found an association between variation in DYX3 SNPs and verbal IQ performance, extending previous links of the DYX3 locus with reading to a broader cognitive scope. Our laboratory has recently conducted a behavioral association and neuroimaging genetic study of the SETBP1 gene, which was previously associated with expressive language function in an isolated population in Russia with a high prevalence of DLD . This population is of interest for investigating a shared genetic cause of DLD because its remote location leads to reduced genetic diversity and increased heritability of traits within the population. A follow-up study revealed a significant association between the SETBP1 gene and reading-relevant skills (e.g., phonological working memory) in a group of typically developing children in the United States BIB010 . Further, we investigated brain activation for the SNP with the strongest association (rs7230525) in a subset of participants who completed an fMRI task that involved reading and listening to words and pseudowords. Our imaging analysis revealed a complex three-way interaction among genotype, word type, and presentation modality in the right inferior parietal lobule. Breaking down this interaction revealed greater activation for more difficult to process printed stimuli (pseudowords > words) for individuals in the genotype group associated with poorer phonological skills BIB010 . Although preliminary, these findings point to a relation between variability in SETBP1 and the role of attentional networks during decoding. Finally, due to the complex nature of reading, it is likely that genes involved in regulating cognitive processes such as memory, executive functioning, and attention may subsequently be related to reading and language. Two such "generalist genes" are COMT, which is involved in dopamine regulation in the prefrontal cortex BIB002 , and BDNF, which regulates a variety of processes involved in brain development and plasticity BIB003 . One recent study showed an association between the COMT Val 158 Met polymorphism (SNP rs4680) and neural activation in the reading circuit (e.g., the left occipito-temporal and superior temporal/middle temporal regions) during a word and pseudoword reading task, in addition to associations with phonological awareness and spelling BIB006 . A second study showed that a common variation at BDNF SNP rs6265 (the BDNF Val 66 Met polymorphism) is associated with reading-related behaviors, including passage comprehension, and neural activation during reading in children  . In light of these reading-related findings for genes associated with more general cognitive factors, it seems important that the field continue to consider the contribution of so-called generalist genes in examinations of the genetic basis of individual differences in reading and language.