Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations

Importance: The relationship between major depressive disorder (MDD) and obesity may stem from shared immuno-metabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight during an active episode.
Objective: To determine whether sub-groups of MDD patients stratified according to the appetite/weight criterion had different degree of genetic overlap with obesity-related traits (body mass index (BMI), C-reactive protein (CRP) and leptin).
Design: Data from the Psychiatric Genomics Consortium assembling genome-wide genotypic and phenotypic measures from 14 datasets.
Setting: Datasets were drawn from case-control, cohort and population-based studies.
Participants: 26,628 samples with established psychiatric diagnoses and GWAS data.
Main outcome and Measures: Lifetime DSM-IV MDD was diagnosed using structured diagnostic instruments. MDD cases were stratified according to DSM appetite/weight symptom in “decreased” (MDDa/w) or “increased” (MDDa/w) sub-groups.
Results: Data included 11,837 MDD cases and 14,791 controls (overall, 59.1% females). Among cases, 45.2% were classified as MDDa/w and 15.8% as MDDa/w. Common genetic variants explained ~10% of the heritability in the two sub-groups. MDDa/w showed a strong and positive genetic correlation with BMI (rg=0.53,se=0.15,p=6.3e-4), while MDDa/w tended to be inversely correlated (rg=-0.28,se=0.14,p=0.055). Furthermore, MDDa/w carried a higher polygenic risk for BMI (OR=1.18,95%CI=1.12-1.25,p=1.6e-10), CRP (OR=1.08,95%CI=1.02-1.13,p=7.3e-3) and leptin (OR=1.09,95%CI=1.06-1.12,p=1.7e-3).
Conclusions and Relevance: The phenotypic interrelationships between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiological mechanisms in ~15% of MDD cases. Development of treatments effectively targeting immuno-metabolic dysregulations may benefit these patients at the cross-road between depression and obesity, two heavily disabling syndromes.