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

Milaneschi Y 1 , Lamers F 1 , Peyrot WJ 1 , Baune BT 2 , Breen G 3 , Dehghan A 4 Show all authors , Forstner AJ 5 , Grabe HJ 6 , Homuth G 7 , Kan C 8 , Lewis C 3 , Mullins N 3 , Nauck M 9 , Pistis G 10 , Preisig M 10 , Rivera M 3 , Rietschel M 11 , Streit F 11 , Strohmaier J 11 , Teumer A 12 , Van der Auwera S 6 , Wray NR 13 , Boomsma DI 14 , Penninx BWJH 1 , CHARGE Inflammation Working Group and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Affiliations 

  • 1 Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands
  • 2 Discipline of Psychiatry, University of Adelaide, Adelaide, Australia
  • 3 Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, England
  • 4 Department of Epidemiology and Biostatistics, Imperial College London, London, England
  • 5 Institute of Human Genetics, University of Bonn, Bonn, Germany
  • 6 Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
  • 7 Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany
  • 8 Department of Psychological Medicine, King's College London, London, England
  • 9 German Centre for Cardiovascular Research, Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany
  • 10 Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland
  • 11 Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 12 Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
  • 13 Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
  • 14 Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands
JAMA Psychiatry, 2017 12 01;74(12):1214-1225.
PMID: 29049554 DOI: 10.1001/jamapsychiatry.2017.3016

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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