Shared genetic links between frontotemporal dementia and psychiatric disorders

Abstract

Background: Epidemiological and clinical studies have suggested comorbidity between frontotemporal dementia (FTD) and psychiatric disorders. FTD patients carrying specific mutations were at higher risk for some psychiatric disorders, and vice versa, implying potential shared genetic etiology, which is still less explored.

Methods: We examined the genetic correlation using summary statistics from genome-wide association studies and analyzed their genetic enrichment leveraging the conditional false discovery rate method. Furthermore, we explored the causal association between FTD and psychiatric disorders with Mendelian randomization (MR) analysis.

Results: We identified a significant genetic correlation between FTD and schizophrenia at both genetic and transcriptomic levels. Meanwhile, robust genetic enrichment was observed between FTD and schizophrenia and alcohol use disorder. Seven shared genetic loci were identified, which were mainly involved in interleukin-induced signaling, synaptic vesicle, and brain-derived neurotrophic factor signaling pathways. By integrating cis-expression quantitative trait loci analysis, we identified MAPT and CADM2 as shared risk genes. MR analysis showed mutual causation between FTD and schizophrenia with nominal association.

Conclusions: Our findings provide evidence of shared etiology between FTD and schizophrenia and indicate potential common molecular mechanisms contributing to the overlapping pathophysiological and clinical characteristics. Our results also demonstrate the essential role of autoimmunity in these diseases. These findings provide a better understanding of the pleiotropy between FTD and psychiatric disorders and have implications for therapeutic trials.

Keywords: Frontotemporal dementia; Genetic correlation; Mendelian randomization; Psychiatric disorders.

Fig. 1

Schematic overview of the analytical workflow. A Illustration of genetic pleiotropy. B Analyzed diseases. C Analytical workflow. D Functional interpretation of the results. FTD, frontotemporal dementia; BD, bipolar disorder; MDD, major depressive disorder; ASD, autism spectrum disorder; ADHD, attention deficit hyperactivity disorder; AUD, alcohol use disorder; OCD, Obsessive compulsive disorder; PTSD, post-traumatic stress disorder; SCZ, schizophrenia; TS, Tourette’s syndrome

Fig. 2

Correlation between FTD and psychiatric diseases. A Genetic correlation. B Expression correlation. Error bars indicate 95% confidence intervals. Red color indicates positive correlation, while blue color indicates negative correlation. Bold P value denotes significance after the Bonferroni correction

Fig. 3

Enrichment plots. Conditional quantile-quantile plots of nominal versus empirical -log₁₀(P) of FTD as a function of significance of association with psychiatric diseases at the levels of -log₁₀(P) > 0, -log₁₀(P) > 1, -log₁₀(P) > 2, and -log₁₀(P) > 3, which correspond to P < 1, P < 0.1, P < 0.01, and P < 0.001, respectively. Dotted lines indicate the expected line under the null hypothesis, and leftward deflection demonstrates degree of enrichment

Fig. 4

Fold-enrichment plots. Enrichment plots of nominal -log₁₀(P) of FTD as a function of significance of association with psychiatric diseases at the levels of -log₁₀(P) ≥ 0, -log₁₀(P) ≥ 1, -log₁₀(P) ≥ 2, and -log₁₀(P) ≥ 3, which correspond to P ≤ 1, P ≤ 0.1, P ≤ 0.01, and P ≤ 0.001, respectively. The horizontal lines indicate the expected line under the null hypothesis, and leftward deflection demonstrates degree of enrichment

Fig. 5

Forest plot showing results from the Mendelian randomization analysis to evaluate potential causal association between FTD and psychiatric disorders. A Mendelian randomization analysis results with FTD as risk factor and psychiatric disorders as outcomes. B Mendelian randomization analysis results with psychiatric disorders as risk factors and FTD as outcome