Mendelian Randomization (MR) Collaborative Study

What is MR?

MR is based on the principle that if a biomarker is causality related to a disease, variation within gene(s) encoding the biomarker should be also associated with the disease. MR uses genetic variants known to influence levels/activity of a biomarker as instrumental variables to examine whether the biomarker is causally linked with an illness. Using genetic variants as marker of exposure overcomes confounding because genetic variants are inherited at random, so are unrelated to potential confounders. This approach has been used to demonstrate a causal role for IL-6 in coronary heart disease (Swerdlow et al. The Lancet 2012) and type 1 diabetes (Ferreira et al. PLoS Genetics 2013) using SNPs in the IL-6R gene (Ch1q21.3) known to regulate activity of IL-6.

Previous studies suggest that concentrations of IL-6 and CRP are elevated in patients with depression and schizophrenia, which tend to normalise after recovery but continue to be elevated in treatment resistant patients. We have previously shown that elevated concentrations of IL-6 and CRP in childhood/ adolescence are associated with increased risk developing depression and psychosis subsequently in adulthood (see Khandaker et al. JAMA Psychiatry 2014 ; Metcalf et al. Brain, Behaviour and Immunity 2017 ; Khandaker et al. Psychological Medicine 2017) .

We have recently shown that a functional IL-6R genetic variant that is known to dampen down inflammation is protective for severe depression and/or psychosis in the ALSPAC birth cohort ( Khandaker et al. Brain, Behaviour and Immunity 2017) . The genetic variant is associated with serum IL-6 and CRP levels but not with any potential confounders, suggesting that previously reported associations between IL-6, depression and schizophrenia may be causal.

Collaborating Partners

ALSPAC birth cohort, UK
Northern Finland Birth Cohort 1986, Finland
Northern Finland Birth Cohort 1966, Finland
UK Biobank

Join the MR Collaboration

Using collaborative meta-analyses of multiple cohorts/datasets, we aim to investigate whether previously reported associations between circulating inflammatory markers (such as IL-6 and CRP), depression and schizophrenia reflect a causal relationship between inflammation and illness or whether these associations could be explained by confounding.

We welcome cohorts or clinical samples with relevant data to participate in our collaborative meta-analyses. The associations to be meta-analysed are: (1) association between serum IL-6/CRP levels and depression/depressive symptoms/schizophrenia; (2) association between IL-6, IL-6R/CRP genetic variants and depression/depressive symptoms/schizophrenia. Please contact the InPsych group if you are interested to collaborate on this research project.

Contact Us

We are happy to hear from prospective group members, research collaborators, participants, media, patients and others. Email:

Our address

Medical Research Council Integrative Epidemiology Unit
University of Bristol
Oakfield House
Oakfield Grove
United Kingdom

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