ONE DIAGNOSIS, MANY ARCHITECTURES: GENOMIC DISSECTION OF DEPRESSION HETEROGENEITY

Overall Abstract Depression is among the most genetically tractable psychiatric disorders, yet its clinical and aetiological heterogeneity remains poorly resolved. This symposium brings together four programmes of work that address depression's heterogeneity from complementary genetic angles: phenotypic subtyping, seasonal variation, psychotic features, and diagnostic precision. Mitchell (QIMR) will examine polygenic prediction of seasonal affective disorder and the influence of seasonality on depression (N=12,613), demonstrating significant associations between SAD and latitude, and a protective chronotype-by-latitude interaction whereby morning chronotype buffers the risk-increasing effect of higher latitude. Polygenic scores for MDD, bipolar disorder, anxiety, vitamin D, and educational attainment are associated with seasonality symptom burden. McGrath (Cambridge) presents the first GWAS meta-analysis of psychotic depression, combining health-record, prescription-based, and self-report definitions across European and African ancestries (> 13,500 cases), testing whether clinical heterogeneity in depression reflects underlying biological heterogeneity. Harder (Karolinska Institutet) reports the largest genetic analysis of neurovegetative MDD subtypes, contrasting AERS+ (hyperphagia/hypersomnia; Neff=47,858) with AERS− (weight loss/insomnia; Neff=156,624). The subtypes are only moderately correlated (rg=0.64) and show sharply divergent metabolic genetic profiles, with subtype differences persisting after BMI conditioning. Merola (KCL) presents a GWAS meta-analysis of DSM-defined depression (106,183 cases, 298,357 controls) using an identical depression phenotype (IDP). Observation that ADHD genetic correlations diverge sharply between broad and DSM-defined depression motivated GWAS by subtraction across seven variant MDD phenotypes, isolating novel loci that more specific to MDD and implicating different biological pathways compare to broader MDD definitions. The IDP-derived PGS also shows superior cross-ancestry prediction in African and South Asian samples compared with larger but less precise GWAS. Together, these studies demonstrate that resolving depression's heterogeneity yields distinct and more interpretable genetic architectures.