Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort
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OBJECTIVE: Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. METHOD: We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. RESULTS: ), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). CONCLUSIONS: The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.
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Variants in IL6R are associated with increased risk of coronary artery disease, rheumatoid arthritis, atrial fibrillation, abdominal aortic aneurysm, asthma, type 1 diabetes, and depression.
“Variants in the IL6R gene have been found to be associated with increased risk of coronary artery disease24, rheumatoid arthritis, atrial fibrillation, and abdominal aortic aneurysm, and with increased susceptibility to asthma, type 1 diabetes, and depression36,37.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [36]
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Drevets, W. C., Wittenberg, G. M., Bullmore, E. T., & Manji, H. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00368-1 · Cited by 348 · see citing works
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Self-citationCytokine Alterations in Schizophrenia: An Updated Review
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“in 2018, finding a strong association between a genetic variant of IL-6 receptor relating to the levels of IL-6 and CRP and development of schizophrenia (119).”
BackgroundThe microbiota-immune axis as a central mediator of gut-brain communication
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Cytokines, Oxidative Stress and Cellular Markers of Inflammation in Schizophrenia
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Self-citationChu, 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
Self-citationPeripheral blood cellular immunophenotype in depression: a systematic review and meta-analysis
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“In cross-sectional analyses, we did not find associations between IL-6 and AD or symptoms of depression (as measured by the SMFQ) at age nine years, nor with CRP at ages 9, 14 and 16 years.”
InfluentialInflammation and depression in young people: a systematic review and proposed inflammatory pathways
Toenders, Y. J., Laskaris, L., Davey, C. G., Berk, M., Milaneschi, Y., Lamers, F., Penninx, B. W. J. H., & Schmaal, L. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01306-8 · Cited by 98 · see citing works
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“…patients therapeutically administered the pro-inflammatory cytokine interferon-α (Musselman et al., 2001), longitudinal epidemiological studies (Khandaker et al., 2018, 2014; Wium-Andersen et al., 2013; Liukkonen et al., 2006), investigations of co-morbid depression in systemic inflammatory…”
BackgroundImpaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia
Zuelli, F. M. D. G. C., & Deakin, J. F. W. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.004 · Cited by 85 · see citing works
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Self-citationEvaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder
Miller, B. J., & Goldsmith, D. R. (2020) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20200015 · Cited by 71 · see citing works
Inflammatory biomarkers in schizophrenia: Implications for heterogeneity and neurobiology
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“Furthermore, inflammatory markers such as CRP, IL-6, and TNF-a have been associated with development or severity of psychiatric disorders such as depression, psychosis, andbipolar disorder (Najjar et al. 2013; Goldstein et al. 2015; Khandaker et al. 2018a, 2018b).”
Dysglycaemia, Inflammation and Psychosis: Findings From the UK ALSPAC Birth Cohort
Perry, B. I., Upthegrove, R., Thompson, A. D., Marwaha, S., Zammit, S., Singh, S. P., & Khandaker, G. M. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby040 · Cited by 55 · see citing works
Self-citationPrenatal and childhood adverse life events, inflammation and depressive symptoms across adolescence
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Self-citationPaternal transgenerational epigenetic mechanisms mediating stress phenotypes of offspring
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Self-citationA longitudinal analysis of cytokines in anorexia nervosa
Dalton, B., Leppänen, J., Campbell, I. C., Chung, R., Breen, G. D., Schmidt, U. H., & Himmerich, H. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.05.012 · Cited by 43 · see citing works
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“Similar methods have been used to study the association between inflammation and other psychiatric outcomes such as schizophrenia and depression (Hartwig et al., 2017; Prins et al., 2016; Khandaker et al., 2018).”
MethodMonocyte count in schizophrenia and related disorders: a systematic review and meta-analysis
Mazza, M. G., Capellazzi, M., Lucchi, S., Tagliabue, I., Rossetti, A., & Clerici, M. (2020) · Acta Neuropsychiatrica · doi:10.1017/neu.2020.12 · Cited by 39 · see citing works
“Moreover, variants of cytokines receptor genes seem to be involved in the pathogenesis of more severe psychosis (Khandaker et al., 2018).”
BackgroundSlaney, C., Sallis, H., Jones, H. J., Dardani, C., CHARGE Inflammation Working Group, Tilling, K. M., Munafo, M. R., Smith, G. D., Mahedy, L., & Khandaker, G. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.02.010 · Cited by 38 · see citing works
“One promising intervention target could be inflammation (Khandaker et al., 2018).”
Self-citationClinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms
Foley, É. M., Parkinson, J. T., Kappelmann, N., & Khandaker, G. M. (2021) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2021.100079 · Cited by 34 · see citing works
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Self-citationLongitudinal population subgroups of CRP and risk of depression in the ALSPAC birth cohort
Osimo, E. F., Stochl, J., Zammit, S., Lewis, G., Jones, P. B., & Khandaker, G. M. (2020) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2019.152143 · Cited by 30 · see citing works
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IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk
Zhang, L., Omarov, M., Xu, L., deGoma, E. M., Natarajan, P., & Georgakis, M. K. (2025) · Nature Cardiovascular Research · doi:10.1038/s44161-025-00700-7 · Cited by 30 · see citing works
“The effect on depression is in line with previous analyses of IL6R genetic instruments 63,64 , as well as reports on tocilizumab in patients with rheumatoid arthritis 65 .”
Microbial metabolites and immune regulation: New targets for major depressive disorder
Merchak, A. R., & Gaultier, A. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100169 · Cited by 29 · see citing works
Unravelling the broader complexity of IL-6 involvement in health and disease
Jenkins, R. L., Hughes, S. T. O., Figueras, A. C., & Jones, S. A. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155684 · Cited by 25 · see citing works
“Genetic studies further identify various risk alleles in IL6 and IL6R associated with major depressive disorders 221-226 .”
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“(2018) [47] IL6R: rs2228145 (Asp358Ala) 9912 unselected participants from the ALSPAC birth cohort Asp358Ala was associated with a reduced risk of severe depression and/or psychosis.”
BackgroundBedeutung von psychosozialen Faktoren in der Kardiologie – Update 2024
Kindermann, I., Köllner, V., Albus, C., Boer, J., Dannberg, G., Fritzsche, K., Gunold, H., Herrmann‐Lingen, C., Leithäuser, B., Meesmann, M., et al. (2024) · Die Kardiologie · doi:10.1007/s12181-024-00708-6 · Cited by 26 · see citing works
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Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis
Kappelmann, N., Perry, B. I., & Khandaker, G. M. (2022) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000322 · Cited by 22 · see citing works
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New approaches in psychiatric drug development
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Immunity and psychiatric disorders: variabilities of immunity biomarkers are they specific?
Dubois, T., Reynaert, C., Jacques, D., Lepièce, B., Patigny, P., & Zdanowicz, N. (2018) · PubMed · Cited by 17 · see citing works
C-Reactive Protein (CRP): A Potent Inflammation Biomarker in Psychiatric Disorders
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“In addition to the reliable edge weights of interest (reported above), accuracy and stability analyses also revealed adequate CS-coef fi cients, ranging between 0.36 and 0.67 (See Supplementary).”
InfluentialSelf-citationENĂTESCU, V. R. (2020) · FARMACIA · doi:10.31925/farmacia.2020.3.14 · Cited by 16 · see citing works
“Several studies have repeatedly detected that higher levels of pro-inflammatory markers such as CRP and interleukin 6 (IL-6) were associated with an increased likelihood of the development of depression [5-7].”
BackgroundSolmi, F., Bulik, C. M., Stavola, B. L. D., Dalman, C., Khandaker, G. M., & Lewis, G. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.07.040 · Cited by 15 · see citing works
Self-citationGenomic-Analysis-Oriented Drug Repurposing in the Search for Novel Antidepressants
Lesmana, M. H. S., Le, N. Q. K., Chiu, W., Chung, K., Wang, C., Irham, L. M., & Chung, M. (2022) · Biomedicines · doi:10.3390/biomedicines10081947 · Cited by 14 · see citing works
“Furthermore, the upregulation and downregulation of IL6 and CRP affect depression severity [70,73].”
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“This gene is known to regulate IL-6 bioactivity; one of the most implicated variants with a direct effect on the expression of the IL6R gene is the Asp358Ala, rs2228145 A > C (formerly known as rs8192284) [26,49].”
BackgroundInfluentialSpanoudaki, M., Papadopoulou, S. Κ., Antasouras, G., Papadopoulos, K., Psara, E., Vorvolakos, T., Solovos, E., Chrysafi, M., Psallas, M., Mentzelou, M., et al. (2024) · Life · doi:10.3390/life14040479 · Cited by 13 · see citing works
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Self-citationInflammatory Markers and Episodic Memory Functioning in Depressive Disorders
Wachowska, K., Szemraj, J., Śmigielski, J., & Gałecki, P. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11030693 · Cited by 13 · see citing works
“It has also been suggested in longitudinal studies that elevated levels of interleukins might precede mental disorders [19,20] and are associated with certain genetic variants [21].”
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“Children with elevated levels of IL-6 and C-reactive protein at 9 years of age are at a higher risk of depression onset by 18 years of age (Khandaker et al., 2018).”
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Kitzbichler, M. G., Aruldass, A. R., Barker, G. J., Wood, T., Dowell, N. G., Hurley, S. A., McLean, J., Correia, M., Clarke, C., Pointon, L. J., et al. (2020) · medRxiv · doi:10.1101/2020.09.09.20191262 · Cited by 9 · see citing works
Sub-clinical systemic inflammation as a determinant of admission duration in psychosis
Blackman, G., DeLaney, J., MacCabe, J. H., Khandaker, G. M., & McGuire, P. K. (2025) · Schizophrenia Research · doi:10.1016/j.schres.2024.12.010 · Cited by 8 · see citing works
“There is growing evidence that immune dysfunction plays a significant role in the pathophysiology of psychotic disorders (Miller et al., 2011; Khandaker et al., 2014; Khandaker et al., 2018).”
Self-citationMonitoring inflammation in psychiatry: Caveats and advice
Khalfallah, O., Barbosa, S., Martinuzzi, E., Davidovic, L., Yolken, R. H., & Glaichenhaus, N. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.09.003 · Cited by 8 · see citing works
Mendelian randomization study on the effect of tumor necrosis factor on schizophrenia
Ma, N., & Wang, R. (2022) · Psychiatric Genetics · doi:10.1097/ypg.0000000000000329 · Cited by 8 · see citing works
Inflammatory pathology in depression and suicide: a mechanistic distillation of clinical correlates
Costanza, A., Amerio, A., Aguglia, A., Magnani, L., Parise, A., Nguyen, K. D., Berardelli, I., Pompili, M., Amore, M., & Serafini, G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1479471 · Cited by 7 · see citing works
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“Carefully selected participants—non-smokers, without obesity, somatic or metabolic comorbidities—enabled the minimisation of known modulators of peripheral IL-6 levels [20,33].”
Primak, A. L., Дмитриевич, Б. К., Rubina, K. A., Станиславович, Д. С., Neyfeld, E. A., Illarionova, M. E., Semina, E. V., Sheleg, D., Va, T., & Karagyaur, M. N. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1361764 · Cited by 6 · see citing works
Francesconi, M., Minichino, A., Khandaker, G. M., Midouhas, E., Lewis, G., & Flouri, E. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.07.035 · Cited by 6 · see citing works
Self-citationGordillo‐Marañón, M., Zwierzyna, M., Charoen, P., Drenos, F., Chopade, S., Shah, T., Engmann, J., Casas, J. P., Chaturvedi, N., Papacosta, O., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.11.377747 · Cited by 6 · see citing works
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“In a Mendelian randomization study involving candidate genes, a functional SNP in the IL-6 receptor promoter was identified, providing estimates of CRP, IL-6, and the severity of depression symptoms in a population cohort study [31].”
Gut Microbes: The Gut Brain Connection
Lynch, C. M. K., O’Riordan, K. J., Clarke, G. A., & Cryan, J. F. (2023) · Springer eBooks · doi:10.1007/978-3-031-46712-7_4 · Cited by 5 · see citing works
Potential links between brown adipose tissue, circadian dysregulation, and suicide risk
Sarlon, J., Partonen, T., & Lang, U. E. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1196029 · Cited by 5 · see citing works
“IL-6 is involved in the physiological homeostasis of neural tissue and in neuropsychiatric disorders (Rothaug et al., 2016; Khandaker et al., 2018).”
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“…those pertaining to inflammatory cytokines, to the etiology, development, and severity of psychiatric disorders (Bull et al., 2009; Felger and Lotrich, 2013; Kalmady et al., 2014; Khandaker et al., 2018; Mikhalitskaya et al., 2023; Momtazmanesh et al., 2019; Rodrigues-A-morim et al., 2018).”
Inflammation, Sickness Behaviour and Depression
Khandaker, G. M., Colasanti, A., & Harrison, N. A. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108539623.008 · Cited by 4 · see citing works
Self-citationWeaving Causal Explanations of Schizophrenia in Urban Areas
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Anti-inflammatory Drugs in the Treatment of Depression
Cavanagh, J. (2023) · Current topics in behavioral neurosciences · doi:10.1007/7854_2023_459 · Cited by 6 · see citing works
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“Within our study, we also found an association between IL6R rs2228145 and compulsions in alcohol-addicted patients and aggressive symptomatology in healthy individuals. rs2228145 has been associated with decreased IL-6-induced C-reactive protein (CRP) levels [32] and depression severity [33].”
Hallab, A., & The Health and Aging Brain Study (HABS-HD) Study Team (2025) · medRxiv · doi:10.1101/2025.04.14.25325836 · Cited by 3 · see citing works
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“Similarly, variants in IL6R have been negatively associated with severe depression and psychosis [8].”
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“Retrospective studies indicate that early-life inflammation may predict later depressive symptoms [15, 36].”
- Authors
- Khandaker, G. M., Zammit, S., Burgess, S., Lewis, G., & Jones, P. B.
- Affiliations
- University of Cambridge (GB)
- University of Bristol (GB)
- University College London (GB)
- Corresponding author
- Khandaker, Golam M.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 69
- Pages
- 264-272
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC5871397
- OpenAlex
- W2774979768
- Cited by
- 118
- References
- 67
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 9 · 2023: 10 · 2022: 11 · 2021: 17 · 2020: 20 · 2019: 18 · 2018: 10
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain Behavior and Immunity (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (204623/Z/16/Z, 102215/2/13/2), 088869/Z/09/Z, 095844/Z/11/Z, 088869, 102215, /Z/11/Z, 100114, 102215/2/13/, 201486 /Z/16/Z, 80354, 201486, 100114/Z/12/Z, 095844)
- NIHR Bristol Biomedical Research Centre
- National Institute for Health and Care Research (NF-SI-0617-10113, NF-SI-0512-10165, RP-PG-0606-1335)
- British Heart Foundation (RG/13/13/30194)
- Academy of Medical Sciences (AMS-SGCL13-Khandaker, 80354)
- University of Bristol (102215/2/13/2, 201486/Z/16/Z)
- Medical Research Council (102215, ref: 102215/2/13/2, MR/L003120/1, 201486/Z/16/Z, 102215/2/13/2, MR/L010305/1, MC_PC_15018)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- IL-6 receptor, rs2228145, depression, psychosis, interleukin-6, C-reactive protein, inflammation, genetic susceptibility, ALSPAC birth cohort, childhood risk factors, postpartum depression
- MeSH terms
- Adolescent, C-Reactive Protein, Child, Depressive Disorder, Female, Genotype, Humans, Male, Psychotic Disorders, Cohort Studies, Interleukin-6, Receptors, Interleukin-6, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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