Shared genetic links between frontotemporal dementia and psychiatric disorders

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Epidemiological and clinical studies suggest comorbidity between frontotemporal dementia (FTD) and psychiatric disorders.
• Specific FTD mutations increase risk for certain psychiatric disorders, and vice versa, hinting at shared genetic underpinnings.
• The shared genetic etiology between FTD and psychiatric disorders remains underexplored.

Purpose of the Study:

• To investigate the genetic correlation and enrichment between FTD and psychiatric disorders.
• To explore potential causal associations between FTD and psychiatric disorders using Mendelian randomization.
• To identify shared genetic loci and genes contributing to the comorbidity.

Main Methods:

• Genome-wide association study (GWAS) summary statistics were used to examine genetic correlation and enrichment.
• Conditional false discovery rate (FDR) method was employed for genetic enrichment analysis.
• Mendelian randomization (MR) analysis was conducted to assess causal associations.

Main Results:

• A significant genetic correlation was found between FTD and schizophrenia at genetic and transcriptomic levels.
• Genetic enrichment was robust between FTD and schizophrenia, and FTD and alcohol use disorder.
• Seven shared genetic loci, primarily involved in interleukin signaling, synaptic vesicle, and BDNF pathways, were identified. MAPT and CADM2 were identified as shared risk genes. MR analysis indicated mutual causation between FTD and schizophrenia.

Conclusions:

• Findings support a shared etiology between FTD and schizophrenia, with common molecular mechanisms underlying overlapping characteristics.
• Autoimmunity plays a crucial role in the pathophysiology of these conditions.
• The study enhances understanding of pleiotropy between FTD and psychiatric disorders, informing therapeutic strategies.