Background: Depression is a highly prevalent and heterogenous disorder. This study aims to determine whether depression with atypical features shows different heritability and different degree of overlap with polygenic risk for psychiatric and immuno-metabolic traits than other depression subgroups.
Methods: Data included 30,069 European ancestry individuals from the UK Biobank who met criteria for lifetime major depression. Participants reporting both weight gain and hypersomnia were classified as ↑WS depression (N = 1,854) and the others as non-↑WS depression (N = 28,215). Cases with non-↑WS depression were further classified as ↓WS depression (i.e. weight loss and insomnia; N = 10,142). Polygenic risk scores (PRS) for 22 traits were generated using genome-wide summary statistics (Bonferroni corrected p=2.1x10-4). Single nucleotide polymorphism (SNP)-based heritability of depression subgroups was estimated.
Results: ↑WS 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-06) vs. non-↑WS depression and ↓WS depression. Leptin PRS was close to the significance threshold (p=2.99e-04), but the effect disappeared when considering GWAS summary statistics of leptin adjusted for BMI. PRS for daily alcohol use was inversely associated with ↑WS depression (OR=0.88, [0.83-0.93], p=1.04e-05) vs. non-↑WS depression. SNP-based heritability was not significantly different between ↑WS depression and ↓WS depression (14.3% and 12.2%, respectively).
Conclusions: ↑WS depression shows evidence of distinct genetic predisposition to immune-metabolic traits and alcohol consumption. These genetic signals suggest that biological targets including immune-cardiometabolic pathways may be relevant to therapies in individuals with ↑WS depression.