The shared genetic architecture of the TDP-43 spectrum: Bridging clinical FTLD and neuropathological endophenotypes.
Maulikkumar Patel, Pawan Kumar, Daniel Western et al.
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In 30 seconds
This inverse-variance fixed-effects and random-effects meta-analysis examined shared genetic associations across neuropathological TDP-43 conditions and clinically diagnosed frontotemporal lobar degeneration (FTLD). Neuropathological datasets included FTLD-TDP subtypes, limbic-predominant age-related TDP-43 encephalopathy (LATE-NC), and hippocampal sclerosis (HS); the analysis also incorporated clinical FTLD. Three loci reached genome-wide significance. GRN and TMEM106B were associated with FTLD-TDP subtypes A and B, LATE-NC, and HS, while MAPT associations spanned most combinations of TDP-43 conditions and clinical FTLD.
Key findings
- Three loci reached genome-wide significance in the meta-analyses.
- GRN (rs5848) and TMEM106B (rs3807865) were associated with FTLD-TDP subtypes A and B, LATE-NC, and HS.
- MAPT, specifically the H1c haplotype, was associated across all examined combinations except FTLD-TDP subtypes B and C, and with clinical FTLD.
- Functional analyses suggested rs3807865 and rs3807866 affect regulatory activity and TMEM106B expression in glial cells.
Why it matters
The findings support genetic overlap across clinical FTLD and several neuropathological TDP-43 conditions, helping connect genetic evidence from differently defined disease categories. They also extend the reported relevance of GRN and TMEM106B beyond FTLD-TDP subtype A and suggest MAPT involvement in the TDP-43 spectrum, which may inform future efforts to understand disease mechanisms.
What to keep in mind
The analysis combines heterogeneous clinical and neuropathological categories; the abstract does not report validation in an independent dataset.