Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | LIMITATIONS AND FUTURE DIRECTIONS <s> Objective ::: The purpose of this investigation was to determine whether there is an association between the putative reading disability (RD) susceptibility gene Doublecortin Domain Containing 2 (DCDC2), and gray matter (GM) distribution in the brain, in a sample of healthy control individuals. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | LIMITATIONS AND FUTURE DIRECTIONS <s> First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | LIMITATIONS AND FUTURE DIRECTIONS <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> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | LIMITATIONS AND FUTURE DIRECTIONS <s> Genetics and neuroscience are two areas of science that pose particular methodological problems because they involve detecting weak signals (i.e., small effects) in noisy data. In recent years, increasing numbers of studies have attempted to bridge these disciplines by looking for genetic factors associated with individual differences in behavior, cognition, and brain structure or function. However, different methodological approaches to guarding against false positives have evolved in the two disciplines. To explore methodological issues affecting neurogenetic studies, we conducted an in-depth analysis of 30 consecutive articles in 12 top neuroscience journals that reported on genetic associations in nonclinical human samples. It was often difficult to estimate effect sizes in neuroimaging paradigms. Where effect sizes could be calculated, the studies reporting the largest effect sizes tended to have two features: (i) they had the smallest samples and were generally underpowered to detect genetic effects... <s> BIB004
Although neuroimaging genetics provide a useful lens for investigating mechanisms that link genes to behavior in neurodevelopmental disorders, several important limitations must be addressed: reproducibility and convergence. Replication of genetic associations with language phenotypes has emerged as one key problem in the extant literature, both in genome-wide and targeted genetic association studies. Specifically, Carrion-Castillo et al. (2016) conducted a genetic association study of reading and language phenotypes with 17 of the most significant SNPs associated with these phenotypes in prior GWAS studies and failed to find any significant associations surviving correction for multiple comparisons in an independent sample from the Netherlands. Accordingly, neuroimaging genetics studies of reading and language should be interpreted with caution, especially because most do not include an independent replication cohort. Indeed, only one of the studies reviewed here included an independent replication cohort for neuroimaging-genetic analysis BIB002 . Furthermore, BIB004 recently raised additional concerns with regard to genetics studies published in neuroimaging journals, namely, issues of sample size and power, calculation of effect size, correction for multiple comparisons, completeness of reporting, and complexity of analysis, in addition to the aforementioned replication problem. Indeed, very few of the studies reviewed here include reports of effect sizes, and several of those reported effect sizes for behavioral-genetic associations, but not imaging genetic associations, making it difficult to interpret the magnitude of reported effects. Additionally, heterogeneity among study samples, measures, and methods likely contributes to a perceived lack of replication in some cases. The neuroimaging-genetic studies reviewed here include a great deal of variance in selection of samples, genetic markers, and analytic approaches that make it difficult to compare findings across studies. For example, BIB003 included a set of behaviorally associated SNPs on DCDC2, but not the DCDC2 intron 2 deletion (DCDC2d) in their neuroimaging genetic analysis. This omission could lead to perceived lack of convergence with previous imaging genetic work on DCDC2 by BIB001 that found an association between gray matter volume and the DCDC2d. Likewise, differences in the acquisition and analysis of neuroimaging data such as examining white matter volume versus white matter microstructure (FA, RD, and AD) represent methodological heterogeneity that limits cross-study comparability. Large-scale studies accounting for such variations are needed to confirm or reject the associations of specific SNPs with reading and language phenotypes. This poses a practical challenge that will require more collaborative cross-disciplinary efforts among researchers to collect the data required for replication. Transparent reporting of methods may also address issues of convergence such that future studies may provide appropriate comparison to existing findings.