NC markers Sox10, p75 and HNK-1 was nearly ablated compared to controls. Treatment with the Wnt/b-catenin antagonist Dkk1 resulted in the ablation of Sox10 and HNK1, but not p75. These results are consistent with the distinct mechanisms of action of Noggin and Dkk1. While Noggin re-specifies the dorsal neuroepithelium into ventral fates, Dkk1 Pimozide inhibits the early steps of NC induction, without altering the axial cell fates or general patterning. In our hands, the dorsal Butenafine hydrochloride neuroepithelium-like clusters are positive for p75. The loss of Sox10 and p75 after the addition of Noggin is consistent with re-specification of dorsal neuroepithelium into ventral neuroepithelium, which typically does not express NC markers. Following the same logic, the addition of Dkk1 may inhibit the NC specification, i.e. appearance of Sox10- and HNK-1-positive emNCSCs, but does not re-specify the dorsal neuroepithelium-like cells, which remain positive for p75. Indeed, the human neural tube cells were found positive for the p75 antigen at the time when the NC is generated. It remains to be determined if this expression is localized to the premigratory neural crest in the dorsal part of human neural tube. In addition to the patterning growth factors discussed above, matrix elasticity may affect hESC differentiation towards NC lineages, similar to that seen for muscle differentiation. It will be important to investigate hESC differentiation into emNCSC using various elasticity matrixes. Finally, we assessed the ability of emNCSCs to migrate in vivo, incorporate into NC derivatives and differentiate appropriately. Grafted emNCSCs efficiently contributed to a variety of NCderived tissues and differentiated appropriately. This finding demonstrates that emNCSCs are competent to contributing to NC derivatives such as the trigeminal ganglia, as cells that do not normally incorporate into the trigeminal ganglia are excluded from the developing ganglia even when they are immediately adjacent to it. Furthermore, emNCSCs contributed to connective tissues including smooth muscle. Therefore, emNCSCs are capable of extensive migration to appropriate NC cell destinations and appear to have the ability to interact with adjacent host NC cells and differentiate efficiently compared to late emNCSCs, in vivo. Critically, transplanted human emNCSCs do not contribute to 
the non-NC cell types, such as CNS tissue. Given the fact that these cells are derived in an antigen free environment the protocol for the derivation of emNCSCs is ideal for generating emNCSC-derived tissues in the culture dish that can subsequently be used for patient treatment. To determine the therapeutic potential of these cells for treating a disease model, we investigated the ability of emNCSCs to colonize aganglionic embryonic guts in organotypic cultures. EmNCSCs were found to be capable of colonizing aganglionic guts and differentiating into neurofilamentpositive cells, presumably enteric neurons, in ex vivo gut cultures. This suggests that emNCSCs might be useful in cell replacement therapies to treat neurocristopathies. Genome-wide significant SNPs in complex traits generally explain only a proportion of the heritability of that disorder. Much of the residual heritability underlying common traits appears to lie in SNPs that do not achieve genome-wide significance, meaning that a substantial proportion of the associated genetic signal in current GWAS is hidden below the genome-wide significance threshold. We know that SNPs that are robustly associated with particular common disorders are not randomly distributed across all genes. Instead, the implicated genes show biologically relevant relationships between each other. This is also true for SNPs in genes for which there is weaker individual evidence for association that falls short of stringent levels of genome-wide significance and statistical approaches have recently been developed to identify sets of functionally related genes containing genetic variants that collectively show evidence for association.