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

Is the genetic overlap with obesity-related traits (body mass index and levels of C-reactive protein and leptin) stronger in patients with major depression and the atypical symptoms of increased appetite and/or weight during an active episode?

The Jama Network: Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations

Data from a large international consortium showed that patients with depression and increased appetite and/or weight (approximately 15% of cases) carried a higher number of genetic risk variants for body mass index and levels of C-reactive protein and leptin.

The established phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms, and development of treatments effectively targeting immunometabolic dysregulations may benefit this subgroup of patients.

Importance  The association between major depressive disorder (MDD) and obesity may stem from shared immunometabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight (A/W) during an active episode.

Objective  To determine whether subgroups of patients with MDD stratified according to the A/W criterion had a different degree of genetic overlap with obesity-related traits (body mass index [BMI] and levels of C-reactive protein [CRP] and leptin).

Design, Setting, and Patients  This multicenter study assembled genome-wide genotypic and phenotypic measures from 14 data sets of the Psychiatric Genomics Consortium. Data sets were drawn from case-control, cohort, and population-based studies, including 26 628 participants with established psychiatric diagnoses and genome-wide genotype data. Data on BMI were available for 15 237 participants. Data were retrieved and analyzed from September 28, 2015, through May 20, 2017.

Main Outcomes and Measures  Lifetime DSM-IV MDD was diagnosed using structured diagnostic instruments. Patients with MDD were stratified into subgroups according to change in the DSM-IV A/W symptoms as decreased or increased.

Results  Data included 11 837 participants with MDD and 14 791 control individuals, for a total of 26 628 participants (59.1% female and 40.9% male). Among participants with MDD, 5347 (45.2%) were classified in the decreased A/W and 1871 (15.8%) in the increased A/W subgroups. Common genetic variants explained approximately 10% of the heritability in the 2 subgroups. The increased A/W subgroup showed a strong and positive genetic correlation (SE) with BMI (0.53 [0.15]; P = 6.3 × 10−4), whereas the decreased A/W subgroup showed an inverse correlation (−0.28 [0.14]; P = .06). Furthermore, the decreased A/W subgroup had a higher polygenic risk for increased BMI (odds ratio [OR], 1.18; 95% CI, 1.12-1.25; P = 1.6 × 10−10) and levels of CRP (OR, 1.08; 95% CI, 1.02-1.13; P = 7.3 × 10−3) and leptin (OR, 1.09; 95% CI, 1.06-1.12; P = 1.7 × 10−3).

Conclusions and Relevance  The phenotypic associations between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability.

The Jama Network: Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations