Shared Peripheral Senescence–Plasticity–Immune Reprogramming Links Triglyceride Metabolism and Bipolar Disorder

Bipolar disorder is closely linked to cardiometabolic disturbance, especially elevated triglycerides, but the biology underlying this association remains unclear. Most transcriptome-wide association studies have emphasized brain tissue and may therefore miss systemic signals arising in peripheral metabolic organs. In this study, S-PrediXcan was applied to genome-wide association summary statistics for four psychiatric disorders—major depressive disorder, bipolar disorder, obsessive-compulsive disorder, and schizophrenia—and five lipid traits—HDL cholesterol, LDL cholesterol, log-transformed triglycerides, non-HDL cholesterol, and total cholesterol. All analyses were restricted to the same five cardiovascular tissues: subcutaneous adipose, liver, skeletal muscle, whole blood, and pancreas. Tissue-specific z scores were combined with Stouffer's method and then projected onto a curated panel of 23 detailed and 13 broad neurobiological pathways.Among the lipid traits, only log-transformed triglycerides showed clear directional concordance with bipolar disorder. At detailed pathway resolution, the Pearson correlation was 0.6465 (p = 1.54 × 10⁻³) and cosine similarity was 0.6226. At broad resolution, the correspondence was even stronger, with Pearson r = 0.7123 (p = 9.34 × 10⁻³) and cosine similarity = 0.6844. The overlap was driven mainly by shared negative loading on telomere maintenance and shared positive loading on long-term potentiation and synaptic plasticity pathways, with further contributions from HLA suppression and vesicular machinery. By contrast, HDL, non-HDL cholesterol, and total cholesterol showed little or no similarity to bipolar disorder, whereas LDL was characterized mainly by inverse relationships. Gene-level correlations were weaker and less specific across all lipid traits.These findings indicate that triglyceride-associated genetic effects in peripheral tissues share a transcriptional architecture with bipolar disorder that is centered on senescence, plasticity, and immune reprogramming. The results support the view that hypertriglyceridemia may be part of bipolar disorder biology rather than merely a secondary consequence, and they point to telomere dynamics and plasticity-related signaling as plausible sites of mechanistic convergence.