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1000 Titel
  • The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study
1000 Autor/in
  1. Perry, Benjamin |
  2. Burgess, Stephen |
  3. Jones, Hannah J. |
  4. Zammit, Stan |
  5. Upthegrove, Rachel |
  6. Mason, Amy |
  7. Day, Felix |
  8. Langenberg, Claudia |
  9. Wareham, Nicholas |
  10. Jones, Peter |
  11. Khandaker, Golam |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-03-12
1000 Erschienen in
1000 Quellenangabe
  • 18(3):e1003455
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1371/journal.pmed.1003455 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954314/ |
1000 Ergänzendes Material
  • https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003455#sec029 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • BACKGROUND: Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. METHODS AND FINDINGS: We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. CONCLUSIONS: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance.
1000 Sacherschließung
lokal Inflammation
lokal Single nucleotide polymorphisms
lokal Inflammatory diseases
lokal Insulin resistance
lokal Genome-wide association studies
lokal Genetics
gnd 4027221-7 Insulin
lokal Schizophrenia
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://orcid.org/0000-0002-1533-026X|https://orcid.org/0000-0001-5365-8760|https://frl.publisso.de/adhoc/uri/Sm9uZXMsIEhhbm5haCBKLiA=|https://frl.publisso.de/adhoc/uri/WmFtbWl0LCBTdGFuIA==|https://frl.publisso.de/adhoc/uri/VXB0aGVncm92ZSwgUmFjaGVsIA==|https://orcid.org/0000-0002-8019-0777|https://orcid.org/0000-0003-3789-7651|https://orcid.org/0000-0002-5017-7344|https://orcid.org/0000-0003-1422-2993|https://orcid.org/0000-0002-0387-880X|https://orcid.org/0000-0002-4935-9220
1000 Label
1000 Förderer
  1. National Institute for Health Research |
  2. Wellcome Trust |
  3. MQ: Transforming Mental Health |
  4. Medical Research Council |
  5. University Hospitals Bristol NHS Foundation Trust |
  6. University of Bristol |
  7. Royal Society, London |
  8. Applied Research Collaboration East of England |
1000 Fördernummer
  1. DRF-2018-11-ST2-018; RP-PG- 0616-20003; 127700
  2. 201486/Z/16/Z
  3. MQDS17/40
  4. MC_PC_17213; MR/S037675/1
  5. -
  6. -
  7. 204623/Z/16/Z
  8. -
1000 Förderprogramm
  1. Doctoral Research Fellowship; Biomedical Research Centre
  2. Intermediate Clinical Fellowship; Sir Henry Dale Fellowship
  3. Data Science Award
  4. Mental Health Data Pathfinder; Therapeutic Target Validation in Mental Health
  5. -
  6. -
  7. Sir Henry Dale Fellowship
  8. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer National Institute for Health Research |
    1000 Förderprogramm Doctoral Research Fellowship; Biomedical Research Centre
    1000 Fördernummer DRF-2018-11-ST2-018; RP-PG- 0616-20003; 127700
  2. 1000 joinedFunding-child
    1000 Förderer Wellcome Trust |
    1000 Förderprogramm Intermediate Clinical Fellowship; Sir Henry Dale Fellowship
    1000 Fördernummer 201486/Z/16/Z
  3. 1000 joinedFunding-child
    1000 Förderer MQ: Transforming Mental Health |
    1000 Förderprogramm Data Science Award
    1000 Fördernummer MQDS17/40
  4. 1000 joinedFunding-child
    1000 Förderer Medical Research Council |
    1000 Förderprogramm Mental Health Data Pathfinder; Therapeutic Target Validation in Mental Health
    1000 Fördernummer MC_PC_17213; MR/S037675/1
  5. 1000 joinedFunding-child
    1000 Förderer University Hospitals Bristol NHS Foundation Trust |
    1000 Förderprogramm -
    1000 Fördernummer -
  6. 1000 joinedFunding-child
    1000 Förderer University of Bristol |
    1000 Förderprogramm -
    1000 Fördernummer -
  7. 1000 joinedFunding-child
    1000 Förderer Royal Society, London |
    1000 Förderprogramm Sir Henry Dale Fellowship
    1000 Fördernummer 204623/Z/16/Z
  8. 1000 joinedFunding-child
    1000 Förderer Applied Research Collaboration East of England |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6426350.rdf
1000 Erstellt am 2021-03-23T16:25:44.358+0100
1000 Erstellt von 315
1000 beschreibt frl:6426350
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet Mon May 17 08:32:56 CEST 2021
1000 Objekt bearb. Mon May 17 08:31:57 CEST 2021
1000 Vgl. frl:6426350
1000 Oai Id
  1. oai:frl.publisso.de:frl:6426350 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
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