The genetics of TDP43-Type-C neurodegeneration: a whole genome sequencing study

Frontotemporal lobar degeneration-TDP Type C (TDP-C) is a unique neurodegenerative disease that starts by attacking the anterior temporal lobe leading to language and/or behavioral syndromes. Current literature on the genetic associations of TDP-C, which we have reviewed here, is uneven and lacks a discernible corpus of robust findings. In our study, we completed genome wide hypothesis-free analyses utilizing artificial Intelligence (AI) to identify rare and common variants associated with TDP-C. We then investigated ANXA11 and TARDBP in a hypothesis-driven analysis, since it was recently shown that TDP-43 and Annexin A11 co-aggregate in all TDP-C cases. 1) Whole genome sequencing was completed to identify pathogenic rare variants prioritized with Illuminas AI-based Emedgene software on 37 confirmed or probable TDP-C cases from the Northwestern-University Cohort. 2) A genome wide association study was then completed to identify common variants associated with TDP-C cases vs 290 controls. 3) Next, common and rare variants in TARDBP, and ANXA11 were investigated in TDP-C vs controls. These analyses identified novel genetic associations between FIG4, UBQLN2, INPP5A, and ANXA11 with TDP-C. Of these FIG4, UBQLN2 and ANXA11 have been associated previously with Amyotrophic lateral sclerosis (ALS). To further assess the observed potential genetic overlap between ALS and TDP-C, we leveraged Mendelian randomization (MR) to assess if the ALS genetic load is associated with TDP-C risk, and found evidence supporting this association. The genetic association of ANXA11 with TDP-C is particularly interesting in view of the recently discovered role of Annexin A11 in forming heterodimers with TDP-43 in all abnormal precipitates, a feature not found in TDP-A or TDP-B, which have no similar predilection for the anterior temporal lobe. In addition to the observed overlap between ALS genetics/ genetic load and TDP-C, it is worth mentioning that FIG4, INPP5A and ANXA11 have been implicated in the inositol metabolism pathway, a feature that remains to be elucidated mechanistically. Our TDP-C genetic literature review identified a surprising paucity of neuropathologically confirmed cases in published investigations. Nonetheless, the literature offers support for some of our findings and reemphasizes the absence of dominant or major pathogenic genes for TDP-C, another feature that sets this neuropathologic entity apart from TDP-A and TDP-B.