5′-upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basal degeneration

Two different H1 sub-haplotypes at chromosome 17q21, H1C and H1E′A, have been associated with progressive supranuclear palsy (PSP) and cortical basal degeneration (CBD). We analyzed the SNPs included in the H1C and H1E′A haplotypes in a large Spanish PSP/CBD series and their interaction with age at onset (AAO). Survival analysis of rs1880753 marker was consistently associated with disease risk and with an earlier age at onset under an additive model. Its location at 160 kb and 50 kb upstream of tau and CRHR1 genes, respectively, suggests that it might act as a cis-element that regulates gene expression. Rs45502095H1 was also associated with AAO under a recessive model. Haplotype analysis failed to replicate the association of H1C and H1E′A haplotypes with PSP/CBD. However, we found a strong association of two H1 sub-haplotypes with PSP and CBD (H1E′C and H1Q), which include MAPT and CRHR1 genes where the risk variant for PSP/CBD could lie.