ROBO1 in callosal development

We found that five SNPs in the putative regulatory region of ROBO1 correlate with white matter density in the posterior part of the CC (splenium), which connects the temporal, parietal, and occipital cortices. We also found that one SNP (rs7631357) was significantly associated with the probability of connections of the body of the CC to parietal cortical regions of the both hemispheres. Although the white matter indices do not directly explain the biophysical factors such as size, diameter, membranes, myein thickness, or packing of axons, our results are the first report of a role for ROBO1 in the general population in the development of a specific structural feature of the human brain. More specifically our results suggest that ROBO1 may be involved in regulating the development of the CC. Unfortunately we did not report the direction of the associations, for example if the most common allele was associated with higher or lower probability of connection. Moreover, our sample set is considered small for a genetic study and although we did not perform actual power analysis, our study is likely to have limited statistical power to detect subtle genetic effects. Nevertheless, our findings can be considered credible as they are convergent with earlier observations of the role of ROBO1 in callosal development in mice. (Andrews et al., 2006; Unni et al., 2012) We did not find associations with FA values of the posterior CC, which is in line with a recent study that estimated that the additive genetic effects on FA values of the posterior CC are not significantly different from zero. (Blokland et al., 2012)

The role of CC in reading or SRD is not entirely clear, although several studies have shown alterations in morphology or microstructure of the white matter in the posterior CC in individuals with SRD. A morphometric study by Rumsey et al. suggested that the splenium and isthmus of the CC are larger in male adults with SRD. (Rumsey et al., 1996) Robichon et al. found that especially the isthmus of the CC was thicker in adults with SRD. (Robichon and Habib, 1998) von Plessen et al. observed that the posterior midbody region of CC was shorter in children with SDR than a controls (von Plessen et al., 2002)

In many studies the integrity of the microstructure of the posterior CC has been reported to be higher in poor readers than in normal readers. Dougherty et al. studied children with different reading abilities and reported that normal readers have lower radial diffusivity and higher FA in the posterior CC than poor readers, possibly reflecting that normal readers have a higher proportion of thick axons and fewer axons in total in this area. Moreover, the FA values correlated negatively with phonological awareness. (Dougherty et al., 2007) Odegrad et al. replicated the negative correlation

between phonological awareness and FA values in the posterior CC and also found a similar effect for decoding skills. (Odegard et al., 2009)

Also positive correlations of reading-related measures with white matter integrity have been reported. In adults who are normal readers the volume of the isthmus and rostrum of the CC positively correlated with phonological decoding efficiency, whereas the white matter integrity of the anterior midbody correlated positively with reading comprehension. (Welcome and Joanisse, 2014) In another study the splenium and isthmus of the CC have been shown to have more white matter in individuals who learnt to read during early adulthood when compared to illiterates. In anatomical analyses of normal readers who learned to read during childhood, the area in the CC that showed increased white matter in late-literates was shown to harbour interhemispheric connections between the angular gyri and dorsal occipital gyri. In functional connectivity analysis, reading was shown to enhance the connectivity between the left and right angular gyri. (Carreiras et al., 2009)

Frye et al. have reported differential associations of white matter organization with subcomponents of reading: orthographic processing skills showed negative correlated and the skills associated with phonological awareness showed positive correlation. (Frye et al., 2008)

Different explanations for the role of CC in SRD have been proposed. According to a hypothesis proposed by Rumsey et al. the more efficiently connected posterior CC may reflect deficient lateralisation of the language networks. (Rumsey et al., 1996) According to this model, the left cortex reading networks inhibit the corresponding areas in the right hemisphere through the white matter tracts in the posterior CC. Therefore abnormal development of the CC would lead to underdevelopment of the left regions and overdevelopment of the right hemisphere. According to an alternative hypothesis a more efficiently connected CC could better mediate compensatory activation of the right hemisphere in SRD. The posterior CC has also been suggested to connect the angular as well as dorsal occipital gyri leading and function in the efficient transfer of phonological and/or visual information during reading. (Carreiras et al., 2009)

Recently, Chechlacz et al. have shown that the CC plays a role in controlling the allocation of spatial attention by regulating interhemispheric dynamics. (Chechlacz et al., 2015) This suggests that alterations in the CC could at least partially explain the deficits in visual attention (Bosse et al., 2007) that are often associated with SRD.

We also observed a trend for association of three ROBO1 SNPs with cortical thickness of the left parietal region. Our finding suggests that if

ROBO1 controls neocortical lamination in humans as the orthologous gene

does in mice (Gonda et al., 2013), the environmental influences are larger on cortical thickness than the effect of ROBO1. Four SNPs in ROBO1 showed association with the AC of parietal region. Asymmetries in the structure of the cerebral cortex have been observed in SRD but they may reflect a consequence of less reading experience. (Bishop, 2013)

6.1.7 OTHER FINDINGS RELATED TO CC IN IMAGING GENETICS OF