There is no evidence that any of the CRH-BP SNPs are functional. Using HapMap data it can be seen that CRH-BP is buffered from adjacent genes by several haplotype blocks indicating that a functional locus is likely to reside within CRH-BP or its environs. One mechanism for functional differences may be a second CRH-BP isoform that has been identified in brain. CRH-BP is highly conserved across vertebrates and in humans encodes a 322 amino acid protein that contains 5 disulphide bonds that are essential for CRH binding (Figure 3). This change in peptide sequence might affect protein folding and stability that might alter CRH binding affinity. Indeed, a C-terminus truncated peptide that shows conformational changes has been detected in the plasma of patients with inflammatory disease [44], [45]. Additionally there are regions of high conservation located within both the 3′-UTR and the introns of this novel 3′-region of the gene which may influence alternative exon usage or mRNA folding (Figure 2). The cross-species conservation is suggestive of function and may explain why we found significant associations with anxiety, alcoholism and
