Neural - adipose crosstalk: Shared genetic architecture of visceral fat and neuropsychiatric disorders

Numerous studies have identified a close association between visceral adipose tissue mass (VAT) and neuropsychiatric disorders (NPDs). Both VAT and NPDs exhibit high heritability, yet their shared genetic architecture remains unclear.

We sought to delineate genetic correlations, locus-level pleiotropy, causal effects, tissue/pathway context, and therapeutic hypotheses linking VAT with ten neuropsychiatric traits (nine NPDs plus cognitive function) using large-scale GWASs.

We conducted genetic correlation, polygenic overlap, colocalization, transcriptome-wide association (TWAS), bidirectional two-sample Mendelian randomization (MR), and pathway-tissue-phenotype-drug enrichment analyses.

We uncovered significant genetic correlations and causal relationships between VAT and NPDs, with a notable bidirectional association pattern. Pleiotropy analysis identified 681 shared independent genomic risk loci, 74 of which are novel, and 19 are causal variants. These pleiotropic loci are predominantly expressed in hypothalamic and related brain regions, influencing lipid metabolism, neurodevelopment, neurotransmitter regulation, and synaptic plasticity via the HPA axis. TWAS analysis prioritized NUCKS1, MED27, LMF1, and YWHAB as novel candidate causal genes. Drug enrichment analysis highlighted 5-HT1A-targeting agents (e.g., vortioxetine) and calcium channel blockers (e.g., CACNA1C) as potential therapies for comorbid NPDs and obesity.

These findings support a shared genetic framework for brain-adipose crosstalk centered on hypothalamic-synaptic mechanisms and highlight potential therapeutic targets for comorbid management.