NEUROVEGETATIVE SYMPTOM DIRECTIONALITY REVEALS METABOLIC DIVERGENCE IN THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER

Major Depressive Disorder (MDD) aggregates individuals with opposing neurovegetative symptom profiles under a single diagnosis, potentially obscuring subtype-specific biology. We performed the largest genetic analysis of MDD subtypes defined by atypical energy-related symptoms (AERS) to-date, classifying cases by the co-occurrence of hypersomnia with increased appetite/weight (AERS⁺) versus insomnia with appetite/weight loss (AERS⁻). Harmonizing data across eight cohorts, we conducted GWAS meta-analyses of AERS⁺ (Effective N = 47,858), AERS⁻ (Effective N = 156,624), and Uncategorised MDD (Effective N = 215,828) against screened controls. We identified 27 genome-wide significant loci across subtypes (4 AERS⁺, 10 AERS⁻, 13 Uncategorised), of which 3 were novel MDD loci. The genetic correlation between AERS⁺ and AERS⁻ was moderate (rg = 0.64), substantially lower than either subtype's correlation with Uncategorised MDD (∼0.88). AERS⁺ showed higher SNP-heritability but lower polygenicity than AERS⁻ and Uncategorised. Two AERS⁺ loci mapped near NEGR1 with ∼3-fold larger effect sizes than in AERS⁻. A case-case GWAS (AERS⁺ vs AERS⁻) identified four genome-wide significant loci at established obesity genes (FTO, ADCY3, TMEM18, NEGR1), with significant SNP-heritability that persisted after genetic BMI adjustment with mtCOJO. Genetic correlations and Mendelian randomization revealed a striking metabolic divergence between subtypes: AERS⁺ showed strong positive genetic correlations with BMI, metabolic syndrome, and an atherogenic-inflammatory metabolite profile (elevated triglycerides, GlycA, branched-chain amino acids; reduced HDL), while AERS⁻ displayed negative or null associations with these traits. BMI-adjusted case-case analyses retained significant genetic correlations with MDD, neuroticism, and loneliness. These findings demonstrate that the directionality of neurovegetative symptoms indexes meaningful genetic heterogeneity within MDD, with metabolic biology as a central but not exclusive axis of differentiation. Our results support preserving symptom-level detail in depression phenotyping and suggest that stratification by neurovegetative profile may improve the resolution of genetic, translational, and treatment-response studies in depression.