Genetic association of major depression with atypical 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.; for the CHARGE Inflammation Working Group and the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1001/jamapsychiatry.2017.3016

Cited by 233Genetic Associations and EpidemiologyTryptophan and brain disordersTreatment of Major Depression

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

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Milaneschi, Yuri, Lamers, Femke, Peyrot, Wouter J., Baune, Bernhard T., Breen, Gerome, Dehghan, Abbas, Forstner, Andreas J., Grabe, Hans J. +17 more·2017·JAMA Psychiatry

DOI 10.1001/jamapsychiatry.2017.3016PMC PMC6396812

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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.

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Obese individuals, particularly those presenting attributes of metabolic syndrome, tend to develop the atypical subtype of depression.
“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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Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort
Chu, A. L., Štochl, J., Lewis, G., Zammit, S., Jones, P. B., & Khandaker, G. M. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.11.007 · Cited by 136 · see citing works
Shared Genetic Loci Between Body Mass Index and Major Psychiatric Disorders
Bahrami, S., Steen, N. E., Shadrin, A. A., O’Connell, K. S., Frei, O., Bettella, F., Wirgenes, K. V., Krull, F., Fan, C. C., Dale, A. M., et al. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2019.4188 · Cited by 132 · see citing works
Genetic heterogeneity and subtypes of major depression
Nguyen, T.-D., Harder, A., Xiong, Y., Kowalec, K., Hägg, S., Cai, N., Kuja-Halkola, R., Dalman, C., Sullivan, P. F., & Lu, Y. (2022) · Molecular Psychiatry · doi:10.1038/s41380-021-01413-6 · Cited by 129 · see citing works
Immuno-metabolic depression: from concept to implementation
Penninx, B. W. J. H., Lamers, F., Jansen, R., Berk, M., Khandaker, G. M., Picker, L. D., & Milaneschi, Y. (2024) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2024.101166 · Cited by 126 · see citing works
The role of monoamine oxidase enzymes in the pathophysiology of neurological disorders
Jones, D. N., & Raghanti, M. A. (2021) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2021.101957 · Cited by 116 · see citing works
Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders
Morris, G., Puri, B. K., Walker, A. J., Maes, M. H. J., Carvalho, A. F., Bortolasci, C. C., Walder, K. R., & Berk, M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.025 · Cited by 112 · see citing works
Co‐shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome
Postolache, T. T., del Bosque‐Plata, L., Jabbour, S. A., Vergare, M. J., Wu, R., & Gragnoli, C. (2019) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32712 · Cited by 107 · see citing works
“The authors concluded that the association may derive from shared immune-metabolic dysregulations (Milaneschi et al., 2017).”
Background
The genetics of depression: successful genome-wide association studies introduce new challenges
Ormel, J., Hartman, C. A., & Snieder, H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0450-5 · Cited by 107 · see citing works
Depression and Obesity: Analysis of Common Biomarkers
Milano, W., Ambrosio, P., Carizzone, F., Biasio, V. D., Munzio, W. D., Foia, M. G., & Capasso, A. (2020) · Diseases · doi:10.3390/diseases8020023 · Cited by 107 · see citing works
“Epidemiological evidence has identified solid associations between depression and obesity [1].”
Background
Metabolomic and inflammatory signatures of symptom dimensions in major depression
Brydges, C. R., Bhattacharyya, S., Dehkordi, S. M., Milaneschi, Y., Penninx, B., Jansen, R., Kristal, B. S., Han, X., Arnold, M., Kastenmüller, G., et al. (2022) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2022.02.003 · Cited by 108 · see citing works
Obesity as a causal risk factor for depression: systematic review and meta-analysis of Mendelian Randomization studies and implications for population mental health
Jokela, M., & Laakasuo, M. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.05.034 · Cited by 101 · see citing works
Characteristics, comorbidities, and correlates of atypical depression: evidence from the UK Biobank Mental Health Survey
Brăilean, A., Curtis, J., Davis, K. A. S., Dregan, A., & Hotopf, M. H. (2019) · Psychological Medicine · doi:10.1017/s0033291719001004 · Cited by 94 · see citing works
Associations of Different Types of Maternal Diabetes and Body Mass Index With Offspring Psychiatric Disorders
Kong, L., Nilsson, I. A. K., Brismar, K., Gissler, M., & Lavebratt, C. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.20787 · Cited by 89 · see citing works
Overweight, obesity, and individual symptoms of depression: A multicohort study with replication in UK Biobank
Frank, P., Jokela, M. M., Batty, G. D., Lassale, C. M., Steptoe, A., & Mika Kivimaki, B. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.07.009 · Cited by 89 · see citing works
Obesity in Adolescents with Psychiatric Disorders
Chao, A. M., Wadden, T. A., & Berkowitz, R. I. (2019) · Current Psychiatry Reports · doi:10.1007/s11920-019-0990-7 · Cited by 84 · see citing works
Functional Connectivity of the Nucleus Accumbens and Changes in Appetite in Patients With Depression
Kroemer, N. B., Opel, N., Teckentrup, V., Li, M., Grotegerd, D., Meinert, S. L., Lemke, H., Kircher, T. T. J., Nenadić, I., Krug, A., et al. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.2464 · Cited by 81 · see citing works
Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption
Badini, I., Coleman, J. R. I., Hagenaars, S. P., Hotopf, M. H., Breen, G. D., Lewis, C. M., & Fabbri, C. (2020) · Psychological Medicine · doi:10.1017/s0033291720002342 · Cited by 74 · see citing works
“%) to estimate heritability considering an expected heritability of 0.10 (Milaneschi et al., 2017), using GCTA-GREML Power Calculator (Visscher et al., 2014).”
BackgroundMethodResultInfluential
The association between plasma tryptophan catabolites and depression: The role of symptom profiles and inflammation
Milaneschi, Y., Allers, K. A., Beekman, A. T. F., Giltay, E. J., Keller, S., Schoevers, R. A., Süßmuth, S. D., Niessen, H. G., & Penninx, B. W. J. H. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.07.007 · Cited by 70 · see citing works
“15 contrast, genetic signature of inflammatory and metabolic alterations characterize specifically atypical-like depressive symptoms(38,39), linked in the present study to increased KYN and QUIN levels.”
Linking atypical depression and insulin resistance-related disorders via low-grade chronic inflammation: Integrating the phenotypic, molecular and neuroanatomical dimensions
Sen, Z. D., Danyeli, L. V., Woelfer, M., Lamers, F., Wagner, G., Sobanski, T., & Walter, M. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.12.020 · Cited by 65 · see citing works
Self-citation
Lifetime and current depression in the German National Cohort (NAKO)
Streit, F., Zillich, L., Frank, J., Kleineidam, L., Wagner, M., Baune, B. T., Klinger-König, J., Grabe, H. J., Pabst, A., Riedel-Heller, S. G., et al. (2021) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2021.2014152 · Cited by 64 · see citing works
“Furthermore, specific definitions, subtypes and aspects of depression may differ in their underlying neurobiology (Milaneschi et al. 2017; Cai et al. 2020; Hagenaars et al. 2020), stressing the need for comprehensive phenotypic assessment.”
Background
Genetic comorbidity between major depression and cardio‐metabolic traits, stratified by age at onset of major depression
Hagenaars, S. P., Coleman, J. R. I., Choi, S. W., Gaspar, H., Adams, M. J., Howard, D. M., Hodgson, K., Traylor, M., Air, T. M., Andlauer, T. F. M., et al. (2020) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32807 · Cited by 61 · see citing works
Self-citation
Obesity and atypical depression symptoms: findings from Mendelian randomization in two European cohorts
Pistis, G., Milaneschi, Y., Vandeleur, C. L., Lasserre, A. M., Penninx, B. W. J. H., Lamers, F., Boomsma, D. I., Hottenga, J., Marques-Vidal, P. M., Vollenweider, P., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01236-7 · Cited by 58 · see citing works
Polygenic risk for immuno-metabolic markers and specific depressive symptoms: A multi-sample network analysis study
Kappelmann, N., Czamara, D., Rost, N., Moser, S., Schmoll, V., Trastulla, L., Štochl, J., Lucae, S., Binder, E. B., Khandaker, G. M., et al. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.03.024 · Cited by 58 · see citing works
The Australian Genetics of Depression Study: New Risk Loci and Dissecting Heterogeneity Between Subtypes
Mitchell, B. L., Campos, A. I., Whiteman, D. C., Olsen, C. M., Gordon, S. D., Walker, A. J., Dean, O. M., Berk, M., Hickie, I. B., Medland, S. E., et al. (2021) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.10.021 · Cited by 47 · see citing works
Ten challenges for clinical translation in psychiatric genetics
Derks, E. M., Thorp, J. G., & Gerring, Z. F. (2022) · Nature Genetics · doi:10.1038/s41588-022-01174-0 · Cited by 54 · see citing works
Regulatory T Cells As Supporters of Psychoimmune Resilience: Toward Immunotherapy of Major Depressive Disorder
Ellul, P., Mariotti‐Ferrandiz, E., Leboyer, M., & Klatzmann, D. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00167 · Cited by 51 · see citing works
The Role of Oxidative Stress in Common Risk Factors and Mechanisms of Cardio-Cerebrovascular Ischemia and Depression
Lin, D., Wang, L., Yan, S., Zhang, Q., Zhang, J. H., & Shao, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/2491927 · Cited by 51 · see citing works
“The former involves factors like poor financial situation, marital status, and life events; the latter have genetic and gender predisposition and other health conditions like obesity [21] and diabetes [22].”
Background
Body Mass Index and risk for onset of mood and anxiety disorders in the general population: Results from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2)
de Wit, L. M., ten Have, M., Cuijpers, P. J., & de Graaf, R. (2022) · BMC Psychiatry · doi:10.1186/s12888-022-04077-w · Cited by 53 · see citing works
A role for vitamin D and omega-3 fatty acids in major depression? An exploration using genomics
Milaneschi, Y., Peyrot, W. J., Nivard, M. G., Mbarek, H., Boomsma, D. I., & Penninx, B. W. J. H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0554-y · Cited by 46 · see citing works
Genetic stratification of depression by neuroticism: revisiting a diagnostic tradition
Adams, M. J., Howard, D. M., Luciano, M., Clarke, T., Davies, G., Hill, W. D., Smıth, D. J., Deary, I. J., Porteous, D. J., & McIntosh, A. M. (2019) · Psychological Medicine · doi:10.1017/s0033291719002629 · Cited by 47 · see citing works
Metabolomics signatures of depression: the role of symptom profiles
de Kluiver, H., Jansen, R., Penninx, B., Giltay, E., Schoevers, R., & Milaneschi, Y. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02484-5 · Cited by 41 · see citing works
“Large-scale genomic studies [14, 15] identified shared genetic liabilities between symptoms of hyperphagia, hypersomnia and weight gain during a depressive episode and traits such as elevated CRP, leptin, and body mass index (BMI), partially explaining their phenotypic connection.”
BackgroundResult
Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults
Diniz, B. S., Reynolds, C. F., Sibille, E. L., Bot, M., & Penninx, B. W. J. H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0541-3 · Cited by 45 · see citing works
Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing
Fabbri, C., Pain, O., Hagenaars, S. P., Lewis, C. M., & Serretti, A. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01059-6 · Cited by 46 · see citing works
Excess body weight and specific types of depressive symptoms: Is there a mediating role of systemic low-grade inflammation?
Chu, K., Cadar, D., Iob, E., & Frank, P. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.11.016 · Cited by 47 · see citing works
Polygenic Scores in Psychiatry: On the Road From Discovery to Implementation
Lewis, C. M., & Vassos, E. (2022) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220795 · Cited by 44 · see citing works
The association between overall and abdominal adiposity and depressive mood: A cross-sectional analysis in 6459 participants
Alshehri, T., Boone, S. C., de Mutsert, R., Penninx, B. W. J. H., Rosendaal, F. R., le Cessie, S., Milaneschi, Y., & Mook-Kanamori, D. O. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104429 · Cited by 44 · see citing works
Insulin resistance and obesity, and their association with depression in relatively young people: findings from a large UK birth cohort
Perry, B. I., Khandaker, G. M., Marwaha, S., Thompson, A., Zammit, S., Singh, S. P., & Upthegrove, R. (2020) · Psychological Medicine · doi:10.1017/s0033291719000308 · Cited by 42 · see citing works
“Taken together with previous research (Khandaker et al., 2014; Miller and Raison, 2016; Khandaker et al., 2018a) which suggests that immune dysfunction could be a target for prevention and treatment of depression, our findings may suggest that other factors also play an important role in increasing…”
Result
Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence
Mocking, R. J. T., Naviaux, J. C., Li, K., Wang, L., Monk, J. M., Bright, A. T., Figueroa, C. A., Schene, A. H., Ruhé, H. G., Assies, J., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-020-01182-w · Cited by 40 · see citing works
Neurovegetative symptom subtypes in young people with major depressive disorder and their structural brain correlates
Toenders, Y. J., Schmaal, L., Harrison, B. J., Dinga, R., Berk, M., & Davey, C. G. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0787-9 · Cited by 39 · see citing works
“In addition, genetic studies have shown that the atypical subtype with increased appetite is associated with a higher polygenic risk score for BMI, leptin and CRP, whereas the typical subtype showed a stronger association with polygenic risk scores for psychiatric disorders such as schizophrenia (24, 25).”
Background
Changes in peripheral blood compounds following psychopharmacological treatment in drug-naïve first-episode patients with either schizophrenia or major depressive disorder: a meta-analysis
Çakici, N., Sutterland, A. L., Penninx, B. W. J. H., de Haan, L., & van Beveren, N. J. M. (2021) · Psychological Medicine · doi:10.1017/s0033291721000155 · Cited by 38 · see citing works
Altered Resting-State Brain Activities in Drug-Naïve Major Depressive Disorder Assessed by fMRI: Associations With Somatic Symptoms Defined by Yin-Yang Theory of the Traditional Chinese Medicine
Xu, Z., Zhang, S., Huang, L., Zhu, X., Zhao, Q., Zeng, Y., Zhou, D., Wang, D., Kuga, H., Kamiya, A., et al. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00195 · Cited by 38 · see citing works
Depression and obesity, data from a national administrative database study: Geographic evidence for an epidemiological overlap
Chauvet‐Gélinier, J., Roussot, A., Cottenet, J., Brindisi, M., Petit, J., Bonin, B., Vergès, B. L., & Quantin, C. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210507 · Cited by 38 · see citing works
“Recent studies have indicated that specific genotypes might contribute to atypical depression features with an associated risk of overweight and obesity, suggesting the relationship between depression and obesity may require special attention to prevent comorbid conditions [14,15].”
Background
Increased serum levels of leptin and insulin in both schizophrenia and major depressive disorder: A cross-disorder proteomics analysis
Çakici, N., Bot, M., Lamers, F., Janssen, T., van der Spek, P. J., de Haan, L., Bahn, S., Penninx, B. W. J. H., & van Beveren, N. J. M. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2019.05.010 · Cited by 37 · see citing works
Peripheral Inflammatory Markers in Subtypes and Core Features of Depression: A Systematized Review
Křenek, P., Hořínková, J., & Bartečků, E. (2023) · Psychopathology · doi:10.1159/000528907 · Cited by 35 · see citing works
Dietary habits, depression and obesity: an intricate relationship to explore in pediatric preventive strategies
Calcaterra, V., Rossi, V., Magenes, V. C., Baldassarre, P., Grazi, R., Loiodice, M., Fabiano, V., & Zuccotti, G. (2024) · Frontiers in Pediatrics · doi:10.3389/fped.2024.1368283 · Cited by 40 · see citing works
Health, pre-disease and critical transition to disease in the psycho-immune-neuroendocrine network: Are there distinct states in the progression from health to major depressive disorder?
Stapelberg, N. J. C., Neumann, D. L., Shum, D., & Headrick, J. P. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.10.014 · Cited by 35 · see citing works
Interventions targeting comorbid depression and overweight/obesity: A systematic review
Cao, B., Xu, J., Li, R., Teopiz, K. M., McIntyre, R. S., & Chen, H. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.07.027 · Cited by 32 · see citing works
Re-evaluating classical body type theories: genetic correlation between psychiatric disorders and body mass index
Ikeda, M., Tanaka, S., Saito, T., Ozaki, N., Kamatani, Y., & Iwata, N. (2018) · Psychological Medicine · doi:10.1017/s0033291718000685 · Cited by 31 · see citing works
“In contrast, more typical features of MDD (decreased appetite and body weight, probably including melancholia) exhibited a nonsignificant trend of negative correlation with BMI (rg = −0.28, p = 0.06; Milaneschi et al. 2017).”
BackgroundInfluential
Childhood maltreatment moderates the influence of genetic load for obesity on reward related brain structure and function in major depression
Opel, N., Redlich, R., Repple, J., Flint, C., Grotegerd, D., Dohm, K., Zaremba, D., Goltermann, J., Steinmann, L. A., Krughöfer, R., et al. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.09.027 · Cited by 30 · see citing works
Genetics and major depressive disorder: clinical implications for disease risk, prognosis and treatment
Fabbri, C., Montgomery, S., Lewis, C. M., & Serretti, A. (2020) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000305 · Cited by 32 · see citing works
Microbiome and immuno-metabolic dysregulation in patients with major depressive disorder with atypical clinical presentation
Refisch, A., Şen, Z. D., Klassert, T. E., Busch, A., Besteher, B., Danyeli, L. V., Helbing, D. L., Schulze‐Späte, U., Stallmach, A., Bauer, M. W., et al. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109568 · Cited by 30 · see citing works
The effects of ketamine on typical and atypical depressive symptoms
Park, L. T., Luckenbaugh, D. A., Pennybaker, S. J., Hopkins, M., Henter, I. D., Lener, M. S., Kadriu, B., Ballard, E. D., & Zarate, C. A. (2020) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.13216 · Cited by 30 · see citing works
Reduced mitochondrial respiration in T cells of patients with major depressive disorder
Gamradt, S., Hasselmann, H., Taenzer, A., Brasanac, J., Stiglbauer, V., Sattler, A., Sajitz-Hermstein, M., Kierszniowska, S., Ramien, C., Nowacki, J., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103312 · Cited by 29 · see citing works
“Given the importance of inflammation in the pathophysiology of MDD (Miller and Raison, 2016) and the crucial role of metabolic programming for immunity (Buck et al., 2017), it seems biologically plausible that metabolic dysfunction in general, and altered immunometabolism in particular, could…”
Background
No bidirectional relationship between depression and periodontitis: A genetic correlation and Mendelian randomization study
Nolde, M., Holtfreter, B., Kocher, T., Alayash, Z., Reckelkamm, S. L., Ehmke, B., Baurecht, H., & Baumeister, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.918404 · Cited by 29 · see citing works
“Intriguingly, the genetic susceptibility for depression is highly correlated with the polygenic risk for systemic inflammation, providing a putative biological pathway for the association with periodontal disease (9).”
Background
Unraveling the genetic architecture of major depressive disorder: merits and pitfalls of the approaches used in genome-wide association studies
Schwabe, I., Milaneschi, Y., Gerring, Z. F., Sullivan, P. F., Schulte, E. C., Suppli, N. P., Thorp, J. G., Derks, E. M., & Middeldorp, C. M. (2019) · Psychological Medicine · doi:10.1017/s0033291719002502 · Cited by 29 · see citing works
“…of the PGC, rg between early-onset and late-onset MDD was approximately 0.99 (Power et al., 2017), and around 0.82 between MDD patients with atypical symptoms of increased appetite and/or weight and those with more typical symptoms of decreased appetite and/or weight (Milaneschi et al., 2017).”
BackgroundInfluential
Investigating whether a combination of higher CRP and depression is differentially associated with worse executive functioning in a cohort of 43,896 adults
Mac Giollabhui, N., Alloy, L. B., Schweren, L. J. S., & Hartman, C. A. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.05.022 · Cited by 25 · see citing works
Big Data Begin in Psychiatry
Weissman, M. M. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.0954 · Cited by 27 · see citing works
Association of depression and obesity with C-reactive protein in Germany: A large nationally representative study
Chae, W. R., Nübel, J., Baumert, J., Gold, S. M., & Otte, C. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.04.024 · Cited by 29 · see citing works
Associations between individual depressive symptoms and immunometabolic characteristics in major depression
Chae, W. R., Baumert, J., Nübel, J., Brasanac, J., Gold, S. M., Hapke, U., & Otte, C. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.03.007 · Cited by 27 · see citing works
Involvement of inflammatory gene expression pathways in depressed patients with hyperphagia
de Kluiver, H., Jansen, R., Milaneschi, Y., & Penninx, B. W. J. H. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0528-0 · Cited by 26 · see citing works
Stability and transition of depression subtypes in late life
Veltman, E. M., Kok, A. A. L., Lamers, F., Stek, M. L., van der Mast, R. C., & Rhebergen, D. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.01.049 · Cited by 25 · see citing works
The associations of self-rated health with cardiovascular risk proteins: a proteomics approach
Bao, X., Borné, Y., Yin, S., Niu, K., Orho‐Melander, M., Nilsson, J. Å., Melander, O., & Engström, G. (2019) · Clinical Proteomics · doi:10.1186/s12014-019-9258-9 · Cited by 24 · see citing works
Subtyping late-life depression according to inflammatory and metabolic dysregulation: a prospective study
Kokkeler, K. J. E., Marijnissen, R. M., Wardenaar, K. J., Rhebergen, D., van den Brink, R. H. S., van der Mast, R. C., & Voshaar, R. C. O. (2020) · Psychological Medicine · doi:10.1017/s0033291720002159 · Cited by 24 · see citing works
“In adult depressed patients an association between atypical depression and metabolic-inflammatory dysregulation was found (Lamers et al., 2013; Milaneschi et al., 2017; Vogelzangs et al., 2014a, 2014b), nevertheless previous findings in older depressed patients were not consistent (Veltman et al.,…”
Result
Serum antioxidant vitamin concentrations and oxidative stress markers associated with symptoms and severity of premenstrual syndrome: a prospective cohort study
Frankel, R. A., Michels, K. A., Kim, K., Kuhr, D. L., Omosigho, U. R., Wactawski‐Wende, J., Levine, L. D., Perkins, N. J., & Mumford, S. L. (2021) · BMC Women s Health · doi:10.1186/s12905-021-01187-7 · Cited by 25 · see citing works
Metabolomics dissection of depression heterogeneity and related cardiometabolic risk
Alshehri, T., Mook‐Kanamori, D. O., van Dijk, K. W., Dinga, R., Penninx, B. W. J. H., Rosendaal, F. R., le Cessie, S., & Milaneschi, Y. (2021) · Psychological Medicine · doi:10.1017/s0033291721001471 · Cited by 25 · see citing works
“Interestingly, earlier (Milaneschi et al., 2017b) and recent (Badini et al., 2020) large-scale genomic studies found that the genetic overlap between BMI, CRP and leptin with depression is symptom specific; this overlap was only found in depressed patients with increased hypersomnia (Badini et al.,…”
Background
Associations of polygenic risks, depression, and obesity-related traits in Taiwan Biobank
Liao, S.-F., Su, C.-Y., Su, M., Chen, C., Chen, C., Lin, K., Pan, Y., Hsiao, P., Chen, P., Huang, Y., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.149 · Cited by 24 · see citing works
Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts
Adams, M. J., Thorp, J. G., Jermy, B. S., Kwong, A. S. F., Kõiv, K., Grotzinger, A. D., Nivard, M. G., Marshall, S., Milaneschi, Y., Baune, B. T., et al. (2024) · Psychological Medicine · doi:10.1017/s0033291724001880 · Cited by 27 · see citing works
“However, a positive genetic correlation between increase in appetite/weight with BMI has previously been shown with PGC cohorts (Milaneschi et al., 2017) and in UKB (Badini et al., 2022), and our findings show that this result holds even when adjusting for genetic overlap with other symptoms.”
Result
Dissection of depression heterogeneity using proteomic clusters
van Haeringen, M., Milaneschi, Y., Lamers, F., Penninx, B. W. J. H., & Jansen, R. (2022) · Psychological Medicine · doi:10.1017/s0033291721004888 · Cited by 22 · see citing works
Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis
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Result
A multivariate genome-wide association study of psycho-cardiometabolic multimorbidity
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Testing Bidirectional Associations Between Childhood Aggression and BMI: Results from Three Cohorts
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How to Utilize Clinical and Genetic Information for Personalized Treatment of Major Depressive Disorder: Step by Step Strategic Approach
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Repeated use of SSRIs potentially associated with an increase on serum CK and CK-MB in patients with major depressive disorder: a retrospective study
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The Co-occurrence of Depression and Obesity
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Exploring the Bidirectional Relationship Between Depression and Obesity
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Exploratory study of association between blood immune markers and cognitive symptom severity in major depressive disorder: Stratification by body mass index status
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INVESTIGATION OF THE GENETIC OVERLAP BETWEEN MAJOR DEPRESSIVE DISORDER AND BODY MASS INDEX IN HAN CHINESE WOMEN
Peterson, R. E., Bigdeli, T. B., van Loo, H., Webb, B. T., Jonathan Flint, C., & Kendler, K. S. (2019) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2017.08.347 · Cited by 1 · see citing works
W41. DISSECTING THE RELATIONSHIP BETWEEN BODY MASS INDEX AND SUBGROUPS OF MAJOR DEPRESSIVE DISORDER DEFINED BY WEIGHT AND SLEEP CHANGE
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T44. FURTHERING UNDERSTANDING OF THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER WITH ATYPICAL ENERGY-RELATED SYMPTOMS: A META-ANALYSIS OF 15,000 CASES
Marshall, S., Harder, A., Thorp, J. G., Adams, M., Breen, G. D., McIntosh, A. M., Milaneschi, Y., Penninx, B. W. J. H., Huider, F., Thomson, P. A., et al. (2024) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2024.08.354
Atypical energy-related symptoms define biologically distinct subtypes of major depressive disorderPreprint
Harder, A., Wang, R., Bergstedt, J., Huider, F., Kurvits, S., Thorp, J. G., Gong, T., Assary, E., Thijssen, A. B., Merola, G. P., et al. (2026) · medRxiv · doi:10.64898/2026.07.02.26357101
Characterisation of major depressive disorder subgroups defined by weight and sleep changes
Marshall, S. (2025) · doi:10.7488/era/6383

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)
DOI: 10.1001/jamapsychiatry.2017.3016
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
Locations: JAMA Psychiatry (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
VU Research Portal (publishedVersion, other-oa)
ResearchOnline - JCU (James Cook University) (submittedVersion)
Research Portal (King's College London) (submittedVersion, other-oa)
Pure Amsterdam UMC (submittedVersion, cc-by)
RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
IRIS (submittedVersion)
Iris (University of Trento) (submittedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
SERVAL (Université de Lausanne) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: National Science Foundation (33CS30-139468, 33CS30-148401, 33CSCO-122661)
Foundation for the National Institutes of Health (1RC2 MH089995)
Amgen
Pfizer
GlaxoSmithKline (3200B0–105993, 33CSCO-122661, 3200B0-118308, 33CS30-148401, 33CS30-139468)
Brigham and Women's Hospital
Massachusetts General Hospital
University of Southern California
Kaiser Permanente
Massachusetts Institute of Technology
Emory University
F. Hoffmann-La Roche
Washington University in St. Louis
Aarhus Universitet
Aarhus Universitetshospital
Johns Hopkins University
University of Texas Southwestern Medical Center
Universität Basel
Virginia Commonwealth University
South London and Maudsley NHS Foundation Trust
Wellcome Trust (104036/Z/14/Z)
QIMR Berghofer Medical Research Institute
Broad Institute
Universitätsmedizin Göttingen
National Institute for Health and Care Research (CL-2017-17-003)
King's College London
University College London
University of Oxford
Newcastle University
European Commission (QLG2-CT-2002-01254, LSHB-CT-2003–503428, 503428, 230374, 01ZZ0103, 01ZZ0403, 01254, 03ZIK012, 01ZZ9603, 334065, LSHB-CT-2003)
University of Glasgow
Cardiff University
Trinity College Dublin
Deutsche Forschungsgemeinschaft (Gr1912/5‐1, 01ZZ0403, 01ZZ9603, 03ZIK012, 01ZZ0103)
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (148401, 122661, 33CSCO, 118308, 105993, 230374, 3200B0, 33CS30, 139468)
Universiteit Leiden (10‐000‐1002)
Rijksuniversiteit Groningen (10‐000‐1002)
Stiftelsen för Strategisk Forskning
James Cook University
Queensland University of Technology
University of Queensland
ZonMw (Middelgroot‐911‐09‐032, 56-464-14192, 184.021.007, 911‐09‐032, 1RC2 MH089995, 10‐000‐1002)
Vrije Universiteit Amsterdam (2008.024)
Bundesministerium für Bildung und Forschung (01ZZ9603, 01ZZ0103, and 01ZZ0403, 01ZX1314G, 01GS08147, 03ZIK012, 01ZZ0403, and 01ZZ0403, 01ZX1314D, 01GS08144, 01ZZ0103, 01ZX1314A, 01ZZ9603)
Albert-Ludwigs-Universität Freiburg
Gentofte Hospital
Dalhousie University
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (184021007, 10-000-1002, 56‐464‐14192, Spinozapremie 56-464-14192)
GGZ inGeest
Rivierduinen
GGZ Friesland
GGZ Drenthe
Nederlands Instituut voor Onderzoek van de Gezondheidszorg (10-000-1002)
Lundbeckfonden
University of Toronto
Università degli Studi di Trento
Karolinska Institutet
Novo Nordisk
Vetenskapsrådet (M-2005-1112)
Westfälische Wilhelms-Universität Münster
Leids Universitair Medisch Centrum
Universitair Medisch Centrum Groningen
Rigshospitalet
Region Hovedstaden
Háskóli Íslands
Dokuz Eylül Üniversitesi
Universidad de Granada
Tartu Ülikool
Rheinische Friedrich-Wilhelms-Universität Bonn
Chinese Society of Clinical Oncology
Siemens Healthineers (01ZZ0103, 01ZZ0403, 01ZZ9603)
H. Lundbeck A/S
Centre for Cognitive Ageing and Cognitive Epidemiology
Universität Greifswald
Ministry of Cultural Affairs
National Institutes of Health (184.021.007, 389875, EU/QLRT-2001-01254, 1s10od018164-01, 1r01mh081802-01, MH66206, N01MH90003, AA13321, MH059542, AA13320, MH059541, DA12854)
School of Medicine, Emory University
University of North Carolina at Chapel Hill
University of California, San Diego
McDonnell Center for Systems Neuroscience
Stanley Center for Psychiatric Research, Broad Institute
Department of Psychiatry, University of Toronto
Medical Research Council (G0701420, MR/K026992/1)
Australian Research Council (FT0991360, FT0991022, 389875, QLG2-CT-2002-01254)
Queensland Brain Institute
Institute of Molecular and Cell Biology
Statens Serum Institut
Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
National Institute on Alcohol Abuse and Alcoholism (R01AA014041, R01AA007535)
National Institute of Mental Health (MH66206, MH068457, N01‐MH‐90003, U01MH109528, MH-081802, RC2MH089995, MH089951, MH109532, U24MH068457, MH085520, R01MH060912, U01MH109532, R01MH059552, RC2MH089951, R01MH061686, MH089995, R01MH080403)
National Institute on Drug Abuse (K08DA019951)
National Cancer Institute
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK066134)
Janssen Research and Development
Institute of Genetics
Division of Cancer Epidemiology and Genetics, National Cancer Institute
NHLBI Division of Intramural Research
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 › 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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Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations

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