ABSTRACT: The genetic basis of chronic traumatic encephalopathy (CTE) is poorly understood. Variation in transmembrane protein 106B (TMEM106B) has been associated with enhanced neuroinflammation during aging and with TDP-43-related neurodegenerative disease, and rs3173615, a missense coding SNP in TMEM106B, has been implicated as a functional variant in these processes. Neuroinflammation and TDP-43 pathology are prominent features in CTE. The purpose of this study was to determine whether genetic variation in TMEM106B is associated with CTE risk, pathological features, and ante-mortem dementia. Eighty-six deceased male athletes with a history of participation in American football, informant-reported Caucasian, and a positive postmortem diagnosis of CTE without comorbid neurodegenerative disease were genotyped for rs3173615. The minor allele frequency (MAF?=?0.42) in participants with CTE did not differ from previously reported neurologically normal controls (MAF?=?0.43). However, in a case-only analysis among CTE cases, the minor allele was associated with reduced phosphorylated tau (ptau) pathology in the dorsolateral frontal cortex (DLFC) (AT8 density, odds ratio [OR] of increasing one quartile?=?0.42, 95% confidence interval [CI] 0.22-0.79, p?=?0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile?=?0.53, 95% CI 0.29-0.98, p?=?0.043), and increased synaptic protein density (??=?0.306, 95% CI 0.065-0.546, p?=?0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR?=?0.40, 95% CI 0.16-0.99, p?=?0.048), but was not associated with TDP-43 pathology. All case-only models were adjusted for age at death and duration of football play. Taken together, variation in TMEM106B may have a protective effect on CTE-related outcomes.
