Genetic overlap between cortical brain morphometry and frontotemporal dementia risk

Abstract

AbstractBackgroundFrontotemporal dementia (FTD) has a complex genetic aetiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown.MethodWe leveraged summary‐based data from genome‐wide association studies (GWASs) and performed LD‐score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolate specific genomic loci with a shared aetiology between FTD and brain structure. We also performed functional annotation, summary‐based‐data Mendelian randomisation for eQTL using human peripheral blood and brain tissue data and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes.ResultPairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified five brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified eight protein‐coding genes. Building upon these findings, we show in a mouse model of FTD that cortical NSF expression decreases with age.ConclusionOur results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the aetiology of FTD.