RegenerativeMedicine.net

Variation in TMEM106B in chronic traumatic encephalopathy

Authors: Jonathan D. Cherry, Jesse Mez, John F. Crary, Yorghos Tripodis, Victor E. Alvarez, Ian Mahar, Bertrand R. Huber, Michael L. Alosco, Raymond Nicks, Bobak Abdolmohammadi, Patrick T. Kiernan, Laney Evers, Sarah Svirsky, Katharine Babcock, Hannah M. Gardner, Gaoyuan Meng, Christopher J. Nowinski, Brett M. Martin, Brigid Dwyer, Neil W. Kowall, Robert C. Cantu, Lee E. Goldstein, Douglas I. Katz, Robert A. Stern, Lindsay A. Farrer, Ann C. McKee, Thor D. Stein

Summary:

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] 0.220.79, p = 0.008), reduced neuroinflammation in the DLFC (CD68 density, OR of increasing one quartile = 0.53, 95% CI 0.290.98, p = 0.043), and increased synaptic protein density (β = 0.306, 95% CI 0.0650.546, p = 0.014). Among CTE cases, TMEM106B minor allele was also associated with reduced ante-mortem dementia (OR = 0.40, 95% CI 0.160.99, 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.

Source: Acta Neuropathologica Communications, 2018; 6 (1)