B3239 - Investigating a causal link between early life infection and schizophrenia - 22/01/2019

B number: 
B3239
Principal applicant name: 
Ruth Mitchell | University of Bristol
Co-applicants: 
Dr Hannah Jones, Dr Carolina Borges, Dr Fernando Hartwig, Georgina Hamilton
Title of project: 
Investigating a causal link between early life infection and schizophrenia
Proposal summary: 

Infections during pregnancy1 and early childhood2 have been linked to increased risk of schizophrenia in observational studies. Inflammation, as measured by interleukin-6 (IL-6) and C-reactive protein (CRP), contribute to host defence against infections3,4. Observational epidemiologic studies suggest that inflammatory biomarkers have a positive association with schizophrenia. Interestingly, we have recently shown that individuals who are genetically predisposed to lower activity of the inflammatory response (i.e. CRP levels and blockade of IL-6 cell signalling) have higher risk of schizophrenia5. This, seemingly contradictive, finding may be explained by a genetically determined decreased inflammatory response resulting in an increased susceptibility to early life infection4. In this project, the link between inflammation, psychosis and early life infection will be explored using publicly available genome-wide association study (GWAS) data and newly measured antibody titres available in the ALSPAC cohort6.

1. Khandaker GM, Zimbron J, Lewis G, Jones PB. Prenatal maternal infection, neurodevelopment and adult schizophrenia: a systematic review of population-based studies. Psychol Med. 2013;43(02):239-257.
2. Khandaker GM, Zimbron J, Dalman C, Lewis G, Jones PB. Childhood infection and adult schizophrenia: A meta-analysis of population-based studies. Schizophr Res. 2012;139(1-3):161-168.
3. Calabrese LH, Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720-727.
4. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111(12):1805-1812.
5. Hartwig FP, Borges MC, Lessa Horta B, Bowden J, Smith GD. Association between genetically elevated levels of inflammatory biomarkers and risk of schizophrenia: a two-sample Mendelian randomisation study. 2017.
6. Mitchell RE, Jones HJ, Yolken RH, et al. Longitudinal serological measures of common infection in the Avon Longitudinal Study of Parents and Children cohort. Wellcome Open Res. 2018;3:49.

Impact of research: 
A deeper understanding into the causes of schizophrenia, inflammation and infection contributing to the wider scientific community
Date proposal received: 
Thursday, 17 January, 2019
Date proposal approved: 
Tuesday, 22 January, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Inflammation, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.