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JAMA Psychiatry. 2017 Dec 1;74(12):1214-1225. doi: 10.1001/jamapsychiatry.2017.3016.

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

Collaborators (183)

Degan A, Wray NR, Ripke S, Mattheisen M, Trzaskowski, Adams MJ., Agerbo E, Air TM, Andlauer TFM, Bacanu SA, Bækvad-Hansen M, Beekman ATF, Bigdeli TB, Binder EB, Blackwood DHR, Bryois J, Buttenschøn HN, Bybjerg-Grauholm J, Cai N, Castelao E, Christensen JH, Clarke TK, Coleman JRI, Colodro-Conde L, Couvy-Duchesne B, Craddock N, Crawford GE, Davies G, Deary IJ, Degenhardt F, Derks EM, Direk N, Eley TC, Escott-Price V, Farhadi Hassan Kiadeh F, Finucane HK, Forstner AJ, Frank J, Gaspar HA, Gill M, Goes FS, Gordon SD, Hall LS, Hansen CS, Hansen TF, Herms S, Hickie IB, Homuth G, Horn C, Hottenga JJ, Ising M, Jansen R, Jorgenson E, Knowles JA, Kohane IS, Kraft J, Kretzschmar WW, Krogh J, Kutalik Z, Li Y, Lind PA, MacIntyre DJ, MacKinnon DF, McGrath P, McGuffin P, Medland SE, Middeldorp CM, Mihailov E, Milaneschi Y, Mondimore FM, Montgomery GW, Mostafavi S, Mullins N, Nauck M, Ng B, Nivard MG, Nyholt DR, O’Reilly PF, Oskarsson H, Owen MJ, Painter JN, Pedersen CB, Pedersen MG, Peterson RE, Pettersson E, Peyrot WJ, Pistis G, Posthuma D, Quiroz JA, Qvist P, Riley BP, Rivera M, Saeed Mirza S, Schoevers R, Schulte EC, Shen L, Shi J, Shyn SI, Sigurdsson E, Sinnamon GCB, Smit JH, Smith DJ, Stefansson H, Steinberg S, Streit F, Strohmaier J, Tansey KE, Teismann H, Teumer A, Thompson W, Thomson PA, Thorgeirsson TE, Traylor M, Treutlein J, Trubetskoy V, Uitterlinden AG, Umbricht D, Van der Auwera S, van Hemert AM, Viktorin A, Visscher PM, Wang Y, Webb BT, Weinsheimer SM, Wellmann J, Wu Y, Xi HS, Witt SH, Yang J, Zhang F, Arolt V, Baune BT, Berger K, Boomsma DI, Cichon S, Dannlowski U, de Geus EJC, DePaulo JR, Domenici E, Domschke K, Esko T, Grabe HJ, Hamilton SP, Hayward C, Heath AC, Kendler KS, Kloiber S, Lewis G, Li QS, Lucae S, Madden PAF, Magnusson PK, Martin NG, McIntosh AM, Metspalu A, Mors O, Mortensen PB, Müller-Myhsok B, Nordentoft M, Nöthen MM, O’Donovan MC, Paciga SA, Pedersen NL, Penninx BWJH, Perlis RH, Porteous DJ, Potash JB, Preisig M, Rietschel M, Schaefer C, Schulze TG, Smoller JW, Stefansson K, Tiemeier H, Uher R, Völzke H, Weissman MM, Werge T, Lewis CM, Levinson DF, Breen G, Børglum AD, Sullivan PF.

Author information

Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, the Netherlands.
Discipline of Psychiatry, University of Adelaide, Adelaide, Australia.
Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, England.
National Institute for Health Research Biomedical Research Centre for Mental Health, King's College London, London, England.
Department of Epidemiology and Biostatistics, Imperial College London, London, England.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Life Brain Center, Department of Genomics, University of Bonn, Bonn, Germany.
Department of Psychiatry, University of Basel, Basel, Switzerland.
Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Department of Psychological Medicine, King's College London, London, England.
South London and Maudsley National Health Service Foundation, London, England.
German Centre for Cardiovascular Research, Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany.
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland.
Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Queensland Brain Institute, University of Queensland, Brisbane, Australia.
Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.



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.


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.


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.

[Indexed for MEDLINE]

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