Background: Frontotemporal dementia (FTD) has a complex genetic aetiology, with mutations in several genes associated with different forms of the disease. However, the precise mechanisms underlying the selective vulnerability of the frontal and temporal brain regions remain unknown. Methods: We 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 phenotypes. Then, we followed up strongly-correlated brain measures with GWAS-pairwise analyses to isolate specific genomic loci with a shared aetiology between FTD and brain structure. We also performed functional annotation and summary-based-data Mendelian randomisation for eQTL data for genes within the overlapping genomic loci of interest using human peripheral blood and brain tissue. We evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Results: Pairwise 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. A genomic region in chromosome 17 was aetiologically shared between FTD, the right inferior parietal surface area, and the right medial orbitofrontal cortical thickness. Functional annotation identified eight protein-coding genes and NSF gene expression shared between FTD and variation in the two brain structure phenotypes. Building upon these findings, we show in a mouse model of FTD that cortical NSF expression decreases with age, corresponding closely with the steadily increasing burden of tau pathology in the cortex. Conclusions: Our 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 and elucidate how NSF expression changes uniquely contribute to risk for and the pathophysiology of frontotemporal lobar degeneration independent of its association with the MAPT locus.
