Compartmentalized Genetic Regulation of Circulating Lipids in Schizophrenia: Evidence from Differential MAGMA and TWAS Patterns Across LDL, TG, HDL, Non-HDL, and TC

Individuals with schizophrenia experience markedly elevated cardiovascular mortality, yet their circulating lipid profile presents a longstanding paradox: reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) are common at first-episode, antipsychotic-naïve stages, while triglycerides (TG) rise consistently and HDL-C shows variability that worsens chronically. We integrated competitive gene-set analysis (MAGMA) of large-scale lipid GWAS summary statistics with brain-specific transcriptome-wide association study (TWAS) using GTEx v8 models across six cortical and subcortical regions to dissect this heterogeneity. Ten overlapping gene sets spanning glial markers, cellular senescence, clonal hematopoiesis, and controls were tested for enrichment across LDL-C, non-HDL-C, TC, logTG, and HDL-C.MAGMA identified strong senescence and clonal hematopoiesis signals for HDL-C, TG, and TC, with only nominal glial contributions to LDL-C and non-HDL-C. Brain TWAS markedly sharpened these patterns: adult microglia and oligodendrocyte marker sets achieved the strongest enrichment specifically for cholesterol fractions (microglia ratios up to 1.63×, p = 1.40 × 10⁻⁴ for TC; oligodendrocyte 1.39×, p = 0.0286 for LDL-C), driven by extreme expression signals in HLA-DRA (caudate Z up to 20.162) and ABCA8 (nucleus accumbens Z up to 12.869). Senescence remained robust for TG and HDL-C (1.02–1.10×, p < 0.01), anchored by EHMT2 and TP53. Housekeeping controls confirmed specificity.These findings refine the glial-hematopoietic-senescence (GHS) framework by demonstrating that early glial reprogramming sequesters cholesterol centrally—explaining naïve-stage hypo-cholesterolemia and white-matter deficits—while progressive senescence impairs TG clearance and HDL function, accounting for later atherogenic shifts. Shared genes such as TP53 and EHMT2 provide molecular convergence. The results position brain glia as central nodes in schizophrenia cardiometabolic risk and open avenues for stage-specific interventions, from glial-supportive agents early to senolytics in chronic illness.