We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
Bibliographical noteFunding Information:
This work was primarily supported by grants from the UK Medical Research Council (MRC; MR/K013807/1 and MR/R005176/1) to J.M. High-performance computing was supported by MRC Clinical Research Infrastructure Funding (MR/M008924/1). The Finnish Twin study was supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and J.K. by the Academy of Finland grants 265240, 263278 and 312073. Financial support for the Sweden twin study was provided by the Karolinska Institutet (ALF 20090183 and ALF 20100305 to Hultman) and NIH (R01 MH52857). Collection of the Sweden case control samples was supported by the Sweden Research Council (Vetenskapsra?det, award D0886501 to PFS) and the NIMH (R01MH077139). Collection of the Irish case control samples was funded by the Wellcome Trust Case Control Consortium 2 project (085475/B/08/Z and 085475/Z/08/Z), the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B), and Science Foundation Ireland (08/IN.1/B1916). The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project is funded by grant agreement HEALTH-F2-2010-241909 (Project EU-GEI) from the European Community's Seventh Framework Programme. The IMPaCT programme at King's College London and the South London and Maudsley NHS Foundation Trust is funded by the National Institute for Health Research (RP-PG-0606-1049). The CRESTAR project received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement 279227 (CRET AR Consortium). EH, ED, LS and JM were supported by MRC grant K013807 to JM. Cardiff University researchers were supported by Medical Research Council (MRC) Centre (G0800509) and Programme Grant (G0801418). Bart PF Rutten is supported by a VIDI grant (number 91718336) from the Netherlands Organisation for Scientific Research. FG is in part supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, the Stanley Medical Research Institute, the Maudsley Charity and the National Institute for Health Research (NIHR) Applied Research Collaboration South London (NIHR ARC South London) at King's College Hospital NHS Foundation Trust. MDF and DQ are funded by an MRC fellowship to MDF (MR/M008436/1). We gratefully acknowledge capital equipment funding from the Maudsley Charity (Grant Ref. 980) and Guy's and St Thomas's Charity (Grant Ref. R130505). This study presents independent research supported by the National Institute for Health Research NIHR BioResource Centre Maudsley at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR, Department of Health and Social Care or King's College London.