Genetic association of major depression with a typical features and obesity-related immunometabolic dysregulations

Milaneschi, Yuri, Lamers, Femke, Peyrot, Wouter J., Baune, Bernhard T., Breen, Gerome, Dehghan, Abbas, Forstner, Andreas J., Grabe, Hans J., Homuth, Georg, Kan, Carol, Lewis, Cathryn, Mullins, Niamh, Nauck, Matthias, Pistis, Giorgio, Preisig, Martin, Rivera, Margarita, Rietschel, Marcella, Streit, Fabian, Strohmaier, Jana, Teumer, Alexander, Van der Auwera, Sandra, Wray, Naomi R., Boomsma, Dorret I., Penninx, Brenda W.J.H., CHARGE Inflammation Working Group, , and Psychiatric Genomics Consrtium, (2017) Genetic association of major depression with a typical features and obesity-related immunometabolic dysregulations. JAMA Psychiatry, 74 (12). pp. 1214-1225.

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Importance: The association between major depressive disorder (MDD) and obesitymay 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 MDDwas 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.

Item ID: 54009
Item Type: Article (Research - C1)
ISSN: 2168-6238
Additional Information:

Grant C.B. Sinnamon, School of Medicine and Dentistry, James Cook University is a member of the Psychiatric Genomics Consrtium.

This study was supported by grants MH085520, MH080403, and U01 MH109532 from the National Institute of Mental Health (NIMH). The Bonn/Mannheim (BoMa) genome-wide association study (GWAS) was supported by the German Federal Ministry of Education and Research, within the context of the National Genome Research Network 2 (NGFN-2); National Genome Research Network plus (NGFNplus); grants 01GS08144 and 01GS08147 from the Integrated Genome Research Network (IG) MooDS; and grants BMBF–01ZX1314A, 01ZX1314D, 01ZX1314D, 01ZX1314G, and 01ZX1314K from Integrated Understanding of Causes and Mechanisms in Mental Disorders, under the auspices of the e:Med Programme. The Cohorte Lausannoise (CoLaus) and psychiatric arm of CoLaus was supported by research grants from GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne; and grants 3200B0-105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, and 33CS30-148401 from the Swiss National Science Foundation. The Genetics of Recurrent Early-Onset Depression Study GWAS project was supported by grants R01 MH061686, MH059542, MH075131, MH059552, MH059541, and MH060912 from the NIMH. Genotyping was performed by the Broad Institute Center for Genotyping and Analysis with support from grant U54 RR020278 from the NIH. The Netherlands Study of Depression and Anxiety (NESDA) and the Netherlands Twin Register (NTR) were supported by the Netherlands Organization for Scientific Research and grants Middelgroot-911-09-032 and Spinozapremie 56-464-14192 from MagW/ZonMW; Center for Medical Systems Biology (Netherlands Organization for Scientific Research Genomics); grant 912-10-02 from ZonMW (Genetic Influences on Stability and Change in Psychopathology From Childhood to Young Adulthood); grant 2008.024 from Netherlands Bioinformatics Centre/BioAssist/RK; grant BBMRI-NL 184.021.007 from Biobanking and Biomolecular Resources Research Infrastructure; VU University’s Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam; and European Research Council Advanced grant 230374 from the European Science Council. The infrastructure for the NESDA study is supported by grant 10-000-1002 from the Geestkracht program of the ZonMw and is supported by participating universities and mental health care organizations (VU University Medical Centre, GGZ inGeest, Arkin, Leiden University Medical Centre, GGZ Rivierduinen, University Medical Centre Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Institute for Quality of Health Care, Netherlands Institute for Health Services Research, and Netherlands Institute of Mental Health and Addiction). Part of the genotyping and analyses were supported by the Genetic Association Information Network of the Foundation for the NIH, Rutgers University Cell and DNA Repository (grant U24 MH068457-06 from the NIMH); the Avera Institute, and grants R01 HD042157-01A and MH081802 and Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995 from the NIH. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is supported by the Netherlands Organization for Scientific Research. Femke Lamers is supported by FP7–Marie Curie Career Integration Grant PCIG12-GA-2012-334065 from the European Union Seventh Framework Programme. The QIMR samples were supported by grants 241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496675, 496739, 552485, 552498, 613602, 613608, 613674, and 619667 from the Australian National Health and MRC; grants FT0991360 and FT0991022 from the Australian Research Council; grant QLG2-CT- 2002-01254 from the FP-5 GenomEUtwin Project; grants AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, MH66206, DA12854, and DA019951 from the NIH; and the Center for Inherited Disease Research. RADIANT was supported by joint grant G0701420 from the UK MRC and GlaxoSmithKline; NIHR Specialist Biomedical Research Centre (BRC) for Mental Health at the South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London; and grant G0000647 from the UK MRC. The GENDEP study was supported by EC Contract LSHB-CT-2003-503428 from the European Commission Framework 6. The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, which is supported by research grants 01ZZ9603, 01ZZ0103, and 01ZZ0403 from the Federal Ministry of Education; the Ministry of Cultural Affairs; and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data were supported by research grant 03ZIK012 from the Federal Ministry of Education and a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. SHIP—Life-Events and Gene-Environment Interaction in Depression (LEGEND) is supported by grant GR 1912/5-1 from the German Research Foundation. Dr Van der Auwera was supported by grant 01ZX1314E from the German Federal Ministry of Education and Research within the framework of the e:Med research and funding concept (IntegraMent). The Sequenced Treatment Alternatives to Relieve Depression Study was supported by contract N01MH90003 from the NIMH to the University of Texas Southwestern Medical Center at Dallas. The TwinGene study was supported by the Swedish Ministry for Higher Education, grant M-2005-1112 from the Swedish Research Council; grants EU/QLRT-2001-01254 and QLG2-CT-2002-01254 from GenomEUtwin; the Swedish Foundation for Strategic Research; and grant U01 DK066134 from the NIH.

Date Deposited: 26 Jun 2018 02:43
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320405 Humoural immunology and immunochemistry @ 50%
52 PSYCHOLOGY > 5202 Biological psychology > 520206 Psychophysiology @ 50%
SEO Codes: 92 HEALTH > 9204 Public Health (excl. Specific Population Health) > 920410 Mental Health @ 50%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 50%
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