MAPT subhaplotypes and chronic traumatic encephalopathy

Abstract

AbstractBackgroundExposure to repetitive head impacts (RHI) is the main risk‐factor for chronic traumatic encephalopathy (CTE), a neurodegenerative disease characterized by perivascular hyperphosphorylated tau deposition. However, the occurrence and severity of CTE varies widely among those with similar RHI exposure, suggesting other factors, including genetics, may contribute. The MAPT gene, which codes for the tau protein, is implicated in other tauopathies, but has not been investigated in CTE. The 17q21.31 region, containing MAPT, includes a megabase‐long inversion (H1/H2; European ancestry only) and copy‐number variations, including α, β and γ segments, which can be characterized as nine segregating structural subhaplotypes. We investigated associations between these subhaplotypes, CTE, and related clinical and neuropathological outcomes.Method458 male brain donors of European ancestry from the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank with known RHI exposure from contact sports and/or military service were evaluated for CTE status, CTE stage (0 = absent; 4 = most severe), semiquantitative tau burden (0 = absent; 3 = most severe) across 11 brain regions and dementia based on informant report. Donors were genotyped on ∼5,000 SNPs across the 17q21.31 region in 2 batches. SHAPEIT and IMPUTE2 were used to phase and impute 12 biallelic surrogate markers and then SHAPEIT was used again to estimate 9 subhaplotypes. We tested the subhaplotype associations with CTE and the above outcomes in regression models adjusted for age at death and 10 principal components of population substructure. Results were meta‐analyzed across batches using the inverse variance method in METAL. Permutation testing was used to account for multiple testing and correlated data.ResultThe imputation quality of the surrogate markers was good (info score:0.516‐0.797). There were no significant associations with CTE status. The H1β1γ1 subhaplotype (frequency = 0.39) was significantly associated with dementia (OR = 1.90; padj = 0.019) and semiquantitative tau burden in the amygdala (OR = 1.53; padj = 0.025), entorhinal cortex (OR = 1.50; padj = 0.047), inferior parietal cortex (OR = 1.51; padj = 0.039), middle frontal cortex (OR = 1.48; padj = 0.045), and superior temporal cortex (OR = 1.67; padj = 0.002). H1β1γ1 was nominally associated with CTE stage (OR = 1.35; p = 0.027).ConclusionThese findings suggest a relationship between MAPT region structural variation and CTE‐related outcomes. Extension in a richly characterized living cohort of elite American football players is ongoing.