Genetic overlap between cortical brain morphometry and frontotemporal dementia risk

Abstract Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwi...

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Bibliographic Details
Published in:Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2023-06, Vol.33 (12), p.7428-7435
Main Authors: Diaz-Torres, Santiago, Ogonowski, Natalia, García-Marín, Luis M, Bonham, Luke W, Duran-Aniotz, Claudia, Yokoyama, Jennifer S, Rentería, Miguel E
Format: Article
Language:English
Subjects:
Animals
Brain - diagnostic imaging
Frontal Lobe
Frontotemporal Dementia - diagnostic imaging
Frontotemporal Dementia - genetics
Genome-Wide Association Study
Humans
Magnetic Resonance Imaging - methods
Mice
Original
Parietal Lobe
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Summary:Abstract Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization 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. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. 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 etiology of FTD.
ISSN:1047-3211
1460-2199
1460-2199
DOI:10.1093/cercor/bhad049