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

Abstract

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 ↑WS depression (N = 1854) 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 = 2.1 × 10-4). 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 = 2.37 × 10-14] and C-reactive protein [OR = 1.11 (1.06-1.17), p = 8.86 × 10-06] v. non-↑WS depression and ↓WS depression. Leptin PRS was close to the significance threshold (p = 2.99 × 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 ↑WS depression [OR = 0.88 (0.83-0.93), p = 1.04 × 10-05] v. 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-cardio-metabolic pathways may be relevant to therapies in individuals with ↑WS depression.

Keywords: Alcohol use; BMI; CRP; atypical depression; cardio-metabolic diseases; polygenic risk scores.

Fig. 1.

Flow chart of the performed analyses. ↑WS, depression with increased weight and sleepiness; ↓WS depression, depression with decreased weight and insomnia.

Fig. 2.

Decile plots showing the odds ratio of ↑WS depression (depression with atypical features) v. depression without ↑WS for BMI PRS (a), C-reactive protein (CRP) PRS (b), daily alcohol use PRS (c) and major depressive disorder (MDD) PRS (d). *p < 0.05; **p < 1 × 10⁻⁰⁵.

Fig. 3.

PRS odds ratio (OR) and 95% confidence intervals of ↑WS depression v. depression without ↑WS. Colors indicate different groups of traits (substance related disorders, major psychiatricdisorders, personality traits, immune metabolic traits). BP, bipolar disorder; SCZ, schizophrenia; ANX, anxiety disorders; PTSD, post-traumatic stress disorder; AN, anorexia nervosa; ALCDEP, alcohol dependence; ALCUSE, daily alcohol use; N_CIGARETTES, n cigarettes per day; CANN, cannabis use lifetime; EXTR, extraversion; NEU, neuroticism; DM2, type 2 diabetes mellitus; CAD, coronary artery disease; ISCH_STROKE, ischaemic stroke; TG, triglycerides; LDL, total LDL cholesterol; HDL, total HDL cholesterol; BMI, body max index; BMI_adjust_leptin, leptin adjusted for BMI; CRP, C-reactive protein.

Fig. 4.

PRS odds ratio (OR) and 95% confidence intervals of ↑WS depression and ↓WS depression compared with healthy controls. BP, bipolar disorder; SCZ, schizophrenia; ANX, anxiety disorders; PTSD, posttraumatic stress disorder; AN, anorexia nervosa; ALCDEP, alcohol dependence; ALCUSE, daily alcohol use; N_CIGARETTES, n cigarettes per day; CANN, cannabis use lifetime; EXTR, extraversion; NEU, neuroticism; DM2, type 2 diabetes mellitus; CAD, coronary artery disease; ISCH_STROKE, ischaemic stroke; TG, triglycerides; LDL, total LDL cholesterol; HDL, total HDL cholesterol; BMI, body max index; BMI_adjust_leptin, leptin adjusted for BMI; CRP, C-reactive protein.