Large-scale analysis of DNA methylation identifies cellular alterations in blood from psychosis patients and molecular biomarkers of treatment-resistant schizophrenia
Authors: Hannon Eilis , Dempster Emma L , Mansell Georgina , Burrage Joe , Bass Nick , Bohlken Marc M , Corvin Aiden , Curtis Charles J , Dempster David , Di Forta Marta , Dinan Timothy G , Donohoe Gary , Gaughran Fiona , Gill Michael , Gillespie Amy , Gunasinghe Cerisse , Hulshoff Hilleke E , Hultman Christina M , Johansson Viktoria , Kahn Rene S , Kaprio Jaakko , Kenis Gunter , Kowalec Kaarina , MacCabe James , McDonald Colm , McQuillin Andew , Morris Derek W , Murphy Kieran C , Mustard Collette , Nenadic Igor , O’Donovan Michael C , Quattrone Diego , Richards Alexander L , Rutten Bart PF , Clair David St , Therman Sebastian , Toulopoulou Timothea , Van Os Jim , Waddington John L ,   Wellcome Trust Case Control Consortium 2,   CREeTable AR consortium, Sullivan Patrick , Vassos Evangelos , Breen Gerome , Collier David Andrew , Murray Robin , Schalkwyk Leonard S , Mill Jonathan 
Published: April 2020

Objective

Psychosis - a complex and heterogeneous neuropsychiatric condition characterized by hallucinations and delusions - is a common feature of schizophrenia. There is evidence for altered DNA methylation (DNAm) associated with schizophrenia in both brain and peripheral tissues. We aimed to undertake a systematic analysis of variable DNAm associated with psychosis, schizophrenia, and treatment-resistant schizophrenia, also exploring measures of biological ageing, smoking, and blood cell composition derived from DNAm data to identify molecular biomarkers of disease.

Methods

We quantified DNAm across the genome in blood samples from 4,483 participants from seven case-control cohorts including patients with schizophrenia or first-episode psychosis. Measures of biological age, cellular composition and smoking status were derived from DNAm data using established algorithms. DNAm and derived measures were analyzed within each cohort and the results combined by meta-analysis.

Results

Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNAm data, with the largest differences seen in treatment-resistant schizophrenia patients. DNAm at 95 CpG sites was significantly different between psychosis cases and controls, with 1,048 differentially methylated positions (DMPs) identified between schizophrenia cases and controls. Schizophrenia-associated DMPs colocalize to regions identified in genetic association studies, with genes annotated to these sites enriched for pathways relevant to disease. Finally, a number of the schizophrenia associated differences were only present in the treatment-resistant schizophrenia subgroup.

Conclusions

We show that DNAm data can be leveraged to derive measures of blood cell counts and smoking that are strongly associated with psychosis. Our DNAm meta-analysis identified multiple DMPs associated with both psychosis and a more refined diagnosis of schizophrenia, with evidence for differential methylation associated with treatment-resistant schizophrenia that potentially reflects exposure to clozapine.