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Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.

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Summary

Genetic factors link brain structure and frontotemporal dementia (FTD) risk. We found shared genetic influences between FTD and specific brain regions, implicating NSF gene expression in disease development.

Keywords:
MRIfrontotemporal dementiagene expressiongenetic overlapneuroimaging

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Area of Science:

  • Neurogenetics
  • Neuroimaging
  • Computational Biology

Background:

  • Frontotemporal dementia (FTD) presents a complex genetic basis with unknown mechanisms of selective brain region vulnerability.
  • Understanding the genetic underpinnings of FTD and its relationship with brain structure is crucial for identifying disease pathways.

Purpose of the Study:

  • To investigate the genetic correlations between FTD risk and cortical brain imaging traits.
  • To identify shared genomic loci between FTD and brain structure.
  • To explore the functional role of candidate genes, including NSF, in FTD pathogenesis.

Main Methods:

  • Genome-wide association studies (GWAS) summary data and LD score regression were used to estimate genetic correlations.
  • Functional annotation and summary-data-based Mendelian randomization (SMR) were performed for eQTL analysis.
  • Gene expression was evaluated in a mouse model of FTD.

Main Results:

  • Significant genetic correlations (rg > 0.45) were found between FTD risk and 5 specific brain regions.
  • Eight protein-coding genes were identified through functional annotation.
  • Cortical N-ethylmaleimide sensitive factor (NSF) expression decreased with age in a mouse model of FTD, implicating NSF in FTD etiology.

Conclusions:

  • Molecular and genetic overlaps exist between brain morphology and FTD risk, particularly involving the right inferior parietal surface area and right medial orbitofrontal cortical thickness.
  • NSF gene expression is implicated in the etiology of frontotemporal dementia.