Atypical depression shares genetic predisposition with immuno-metabolic traits: a population-based study
BackgroundDepression is a highly prevalent and heterogenous disorder. Clinical heterogeneity may reflect different underlying biological mechanisms. This study aims to determine whether atypical depression shows higher heritability and different degree of overlap with polygenic risk for cardio- and immuno- metabolic traits than non-atypical depression. MethodsData included 30,069 individuals from the UK Biobank who met criteria for lifetime major depression. Participants reporting both hypersomnia and weight gain were classified as atypical cases (N = 1,854), and the others as non-atypical cases (N = 28,215). Non-atypical cases were further classified as typical depression (i.e. insomnia and weight loss; N = 10,142). Polygenic risk scores (PRS) for 21 traits were generated using genome-wide summary statistics (Bonferroni corrected p=2.2x10-4). Single nucleotide polymorphism (SNP)-based heritability of atypical and typical depression was estimated. ResultsAtypical depression had a higher polygenic risk for BMI (OR=1.20, [1.15-1.26], p=2.37e-14), and C-reactive protein (OR=1.11, [1.06-1.17], p=8.86e-14) vs. non-atypical cases. Leptin PRS was very close to the significance threshold (p=4.13e-04), but the effect disappeared when considering GWAS summary statistics of leptin adjusted for BMI. PRS for daily alcohol use was inversely associated with atypical depression (OR=0.88, [0.84-0.93], p=1.04e-05) vs. non-atypical depression. SNP-based heritability on the liability scale was not significantly different between atypical and typical depression (5.2% and 4.5%, respectively). ConclusionsAtypical depression shows evidence of distinct genetic predisposition to immune-metabolic traits in line with the previous literature. These genetic signals suggest that biological targets including cardiometabolic or immune pathways may be germane to therapies in individuals with atypical depression.
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