Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing

Area of Science:

• Neurogenetics
• Genomics
• Neurodegenerative Diseases

Background:

• Frontotemporal lobar degeneration with TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with limited identified risk loci.
• Understanding the genetic architecture of FTLD-TDP is crucial for developing effective treatments.

Purpose of the Study:

• To conduct a comprehensive genome-wide association study (GWAS) for FTLD-TDP.
• To identify novel genetic risk factors and subtype-specific loci for FTLD-TDP.
• To explore the role of rare variants in FTLD-TDP pathogenesis.

Main Methods:

• Genome-wide association study (GWAS) meta-analysis including 985 FTLD-TDP patients and 3,153 controls from the International FTLD-TDP Whole-Genome Sequencing Consortium and the Dementia-seq cohort.
• Subgroup analyses for FTLD-TDP pathological subtypes (A, B, and C).
• Rare variant analysis to identify novel risk genes.

Main Results:

• Confirmed UNC13A as the strongest FTLD-TDP risk factor and identified TNIP1 as a novel risk factor.
• Identified genome-wide significant loci specific to FTLD-TDP subtypes A, B, and C, with tissue and cell-type enrichment.
• Confirmed TBK1 and identified C3AR1, SMG8, VIPR1, RBPJL, L3MBTL1, and ANO9 as novel subtype-specific FTLD-TDP risk genes.

Conclusions:

• FTLD-TDP subtypes may have distinct genetic etiologies.
• Innate and adaptive immunity and notch signaling pathways are implicated in FTLD-TDP.
• Identified genetic factors have potential diagnostic and therapeutic implications for FTLD-TDP.