O1‐07‐06: A genome‐wide association study of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)

Background. PSP and CBD are related disorders with prominent tau neuropathology. While both are seemingly sporadic, previous work showed that single nucleotide polymorphisms (SNPs) in or near MAPT influence risk for developing these two diseases. MAPT encodes the protein tau that is in fibrillary tangles in tauopathies including Alzheimer's disease. We performed a genome-wide association study to identify additional genes that contribute to susceptibility to PSP and CBD. Methods. We collected DNA from autopsy-documented PSP (n = 1,212) and CBD (n = 168) cases and genotyped these samples using an Illumina 660Quad array. We used principal component analysis to remove non-Caucasian samples and identity by state to detect duplicate and familial samples. We used genetic matching to identify 3 controls for each case. After filtering, 1,234 cases were matched to 3,317 controls. The genomic inflation factor (based on median chi-squared) was 1.0125. Results. Multiple SNPs in or near MAPT generated genome wide significant results (e.g. rs8070723, p = 6.28E-61) for the entire sample (PSP + CBD). For PSP or CBD alone, the same site yielded significant evidence for association (2.78E-56 and 3.62E-08, respectively). Four other sites yielded genome-wide evidence for a significant association. On chromosome 1, multiple SNPs at the genes MR1 and STX6 were significant (e.g. rs1411478, 7.33E-12). On chromosome 3, SNPs at MOBP gave significant results (e.g. rs9820623, 3.43E-10). On chromosome 11, SNPs in or near FAM76B, CEP57, and MTMR2 give significant results (e.g. rs1727165, 9.13E-08). On chromosome 12, SNPs in or near Nell2 yielded significant results (e.g. rs7299371, 6.47E-08). Conclusion. MAPT is a susceptibility gene for both PSP and CBD. In addition, four other loci contribute to PSP/CBD risk. To replicate and extend these findings, we are genotyping an independent group of 139 PSP and 24 CBD autopsy cases, and 1,153 cases with a clinical diagnosis of PSP. These new risk loci will provide insight not only into PSP and CBD pathogenesis, but will also contribute to understanding other tauopathies such as Alzheimer's disease. Funded by the CurePSP Society, the Charles D. Peebler Jr. PSP and CBD Genetics Program, and NIH.