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Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations
Open accessAbstract
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.
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“Obese individuals, particularly those presenting attributes of metabolic syndrome (abdominal obesity, hyperglycemia, hypertension, elevated triglycerides), tend to develop the atypical subtype [9] (Box 1).”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [9]
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“…within these pathways, suggesting that the obesity-related genetic effects on depression may vary by symptom subtype—such as the increased-appetite or atypical depression symptom—rather than reflecting a uniform bidirectional genetic liability (Lasserre et al., 2014; Milaneschi et al., 2017).”
Metadata
- Authors
- Milaneschi, Y., Lamers, F., Peyrot, W. J., Baune, B. T., Breen, G., Dehghan, A., Forstner, A. J., Grabe, H. J., Homuth, G., Kan, C., Lewis, C., Mullins, N., Nauck, M., Pistis, G., Preisig, M., Rivera, M., Rietschel, M., Streit, F., Strohmaier, J., Teumer, A., Van der Auwera, S., Wray, N. R., Boomsma, D. I., Penninx, B. W. J. H., & for the CHARGE Inflammation Working Group and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
- Affiliations
- Amsterdam Neuroscience (NL)
- The University of Adelaide (AU)
- King's College London (GB)
- Imperial College London (GB)
- University of Bonn (DE)
- Universitätsmedizin Greifswald (DE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Universidad de Granada (ES)
- Heidelberg University (DE)
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
- The University of Queensland (AU)
- Vrije Universiteit Amsterdam (NL)
- Corresponding author
- Milaneschi, Yuri
- ORCID
- Milaneschi, Yuri
- Lamers, Femke
- Peyrot, Wouter J.
- Baune, Bernhard T.
- Breen, Gerome
- Dehghan, Abbas
- Grabe, Hans J.
- Homuth, Georg
- Kan, Carol
- Lewis, Cathryn
- Mullins, Niamh
- Pistis, Giorgio
- Preisig, Martin
- Rivera, Margarita
- Rietschel, Marcella
- Streit, Fabian
- Strohmaier, Jana
- Teumer, Alexander
- Wray, Naomi R.
- Boomsma, Dorret I.
- Penninx, Brenda W. J. H.
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2017-12-01
- Volume
- 74
- Issue
- 12
- Pages
- 1214
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC6396812
- OpenAlex
- W2766503838
- Cited by
- 233
- References
- 56
- Citations by year
- 2026: 15 · 2025: 30 · 2024: 15 · 2023: 29 · 2022: 33 · 2021: 41 · 2020: 31 · 2019: 29 · 2018: 9 · 2017: 1
- FWCI
- 12.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
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- Foundation for the National Institutes of Health (1RC2 MH089995)
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- School of Medicine, Emory University
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- Department of Psychiatry, University of Toronto
- Medical Research Council (G0701420, MR/K026992/1)
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- Institute of Molecular and Cell Biology
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- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- major depressive disorder, atypical depression, obesity, genetic correlation, body mass index, C-reactive protein, leptin, polygenic risk, genetic overlap, Psychiatric Genomics Consortium, heritability
- MeSH terms
- Adult, C-Reactive Protein, Depressive Disorder, Major, Major Depressive Disorder, Female, Humans, International Cooperation, Male, Obesity, Psychiatric Status Rating Scales, Weight Gain, Body Mass Index, Genetic Predisposition to Disease, Diagnostic and Statistical Manual of Mental Disorders, Genome-Wide Association Study, Craving
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