Work

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

Year: 2026

Type: article

Abstract: • This is the first study to systematically explore the shared genetic architecture between VAT and NPDs using large-scale GWAS summary statistics and multi-method analyses. • Pleiotropic analysis identified 27,790 significant SNVs across six trait pairs, revealing 74 novel loci and 19 colocalized variants, with bidirectional MR confirming causal effects. • TWAS highlighted 43 genes, including novel candidates NUCKS1, MED27, LMF1, and YWHAB ; several (e.g., DHRS11, RNF123, SH2B1 ) were reinforced by tissue-specific colocalization. • 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. • Minimal overlap in enriched pathways between concordant and discordant gene sets suggests distinct hypothalamic-synaptic pleiotropic mechanisms. • Drug enrichment analysis highlighted 5-HT1A-targeting agents and calcium channel blockers as promising therapeutic candidates for mitigating and treating VAT-NPDs comorbidities. 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.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2026.01.080