Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption

Background Depression is a highly prevalent and heterogeneous 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 up arrow WS depression (N = 1854) and the others as non-up arrow WS depression (N = 28 215). Cases with non-up arrow WS depression were further classified as down arrow 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 = 2.1 x 10(-4)). Single-nucleotide polymorphism (SNP)-based heritability of depression subgroups was estimated. Results up arrow WS depression had a higher polygenic risk for BMI [OR = 1.20 (1.15-1.26), p = 2.37 x 10(-14)] and C-reactive protein [OR = 1.11 (1.06-1.17), p = 8.86 x 10(-06)] v. non-up arrow WS depression and down arrow WS depression. Leptin PRS was close to the significance threshold (p = 2.99 x 10(-04)), but the effect disappeared when considering GWAS summary statistics of leptin adjusted for BMI. PRS for daily alcohol use was inversely associated with up arrow WS depression [OR = 0.88 (0.83-0.93), p = 1.04 x 10(-05)] v. non-up arrow WS depression. SNP-based heritability was not significantly different between up arrow WS depression and down arrow WS depression (14.3% and 12.2%, respectively). Conclusions up arrow WS depression shows evidence of distinct genetic predisposition to immune-metabolic traits and alcohol consumption. These genetic signals suggest that biological targets including immune-cardio-metabolic pathways may be relevant to therapies in individuals with up arrow WS depression.