DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

E. Hannon; E.L. Dempster; G. Mansell; J. Burrage; N. Bass; M.M. Bohlken; A. Corvin; C.J. Curtis; D. Dempster; M. Di Forti; T.G. Dinan; G. Donohoe; F. Gaughran; M. Gill; A. Gillespie; C. Gunasinghe; H.E. Hulshoff; C.M. Hultman; V. Johansson; R.S. Kahn; J. Kaprio; G. Kenis; K. Kowalec; J. MacCabe; C. McDonald; A. McQuillin; D.W. Morris; K.C. Murphy; C.J. Mustard; I. Nenadic; M.C. O'Donovan; D. Quattrone; A.L. Richards; B.P. Rutten; D. St Clair; S. Therman; T. Toulopoulou; J. Van Os; J.L. Waddington; P. Sullivan; E. Vassos; G. Breen; D.A. Collier; R.M. Murray; L.S. Schalkwyk; J. Mill; CRESTAR Consortium; Wellcome Trust Case Control Consortium (WTCCC)

doi:10.7554/eLife.58430

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

E. Hannon, E.L. Dempster, G. Mansell, J. Burrage, N. Bass, M.M. Bohlken, A. Corvin, C.J. Curtis, D. Dempster, M. Di Forti, T.G. Dinan, G. Donohoe, F. Gaughran, M. Gill, A. Gillespie, C. Gunasinghe, H.E. Hulshoff, C.M. Hultman, V. Johansson, R.S. KahnJ. Kaprio, G. Kenis, K. Kowalec, J. MacCabe, C. McDonald, A. McQuillin, D.W. Morris, K.C. Murphy, C.J. Mustard, I. Nenadic, M.C. O'Donovan, D. Quattrone, A.L. Richards, B.P. Rutten, D. St Clair, S. Therman, T. Toulopoulou, J. Van Os, J.L. Waddington, P. Sullivan, E. Vassos, G. Breen, D.A. Collier, R.M. Murray, L.S. Schalkwyk, J. Mill^*, CRESTAR Consortium, Wellcome Trust Case Control Consortium (WTCCC)

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

We performed a systematic analysis of blood DNA methylation profiles from 4483 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 1048 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.

Original language	English
Article number	e58430
Number of pages	31
Journal	Elife
Volume	10
DOIs	https://doi.org/10.7554/eLife.58430
Publication status	Published - 26 Feb 2021

Keywords

1ST-EPISODE PSYCHOSIS
BLOOD
BURDEN
DISEASE
HIGH-POTENCY CANNABIS
HUMAN BRAIN-TISSUE
METHYLOMIC VARIATION
RISK
TRAIT
WIDE ASSOCIATION

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10.7554/eLife.58430Licence: CC BY

Cite this

Hannon, E., Dempster, E. L., Mansell, G., Burrage, J., Bass, N., Bohlken, M. M., Corvin, A., Curtis, C. J., Dempster, D., Di Forti, M., Dinan, T. G., Donohoe, G., Gaughran, F., Gill, M., Gillespie, A., Gunasinghe, C., Hulshoff, H. E., Hultman, C. M., Johansson, V., ... Wellcome Trust Case Control Consortium (WTCCC) (2021). DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia. Elife, 10, Article e58430. https://doi.org/10.7554/eLife.58430

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title = "DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia",

abstract = "We performed a systematic analysis of blood DNA methylation profiles from 4483 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 1048 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.",

keywords = "1ST-EPISODE PSYCHOSIS, BLOOD, BURDEN, DISEASE, HIGH-POTENCY CANNABIS, HUMAN BRAIN-TISSUE, METHYLOMIC VARIATION, RISK, TRAIT, WIDE ASSOCIATION",

author = "E. Hannon and E.L. Dempster and G. Mansell and J. Burrage and N. Bass and M.M. Bohlken and A. Corvin and C.J. Curtis and D. Dempster and {Di Forti}, M. and T.G. Dinan and G. Donohoe and F. Gaughran and M. Gill and A. Gillespie and C. Gunasinghe and H.E. Hulshoff and C.M. Hultman and V. Johansson and R.S. Kahn and J. Kaprio and G. Kenis and K. Kowalec and J. MacCabe and C. McDonald and A. McQuillin and D.W. Morris and K.C. Murphy and C.J. Mustard and I. Nenadic and M.C. O'Donovan and D. Quattrone and A.L. Richards and B.P. Rutten and {St Clair}, D. and S. Therman and T. Toulopoulou and {Van Os}, J. and J.L. Waddington and P. Sullivan and E. Vassos and G. Breen and D.A. Collier and R.M. Murray and L.S. Schalkwyk and J. Mill and {CRESTAR Consortium} and {Wellcome Trust Case Control Consortium (WTCCC)}",

year = "2021",

month = feb,

day = "26",

doi = "10.7554/eLife.58430",

language = "English",

volume = "10",

journal = "Elife",

issn = "2050-084X",

publisher = "eLife Sciences Publications, Ltd",

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Hannon, E, Dempster, EL, Mansell, G, Burrage, J, Bass, N, Bohlken, MM, Corvin, A, Curtis, CJ, Dempster, D, Di Forti, M, Dinan, TG, Donohoe, G, Gaughran, F, Gill, M, Gillespie, A, Gunasinghe, C, Hulshoff, HE, Hultman, CM, Johansson, V, Kahn, RS, Kaprio, J, Kenis, G, Kowalec, K, MacCabe, J, McDonald, C, McQuillin, A, Morris, DW, Murphy, KC, Mustard, CJ, Nenadic, I, O'Donovan, MC, Quattrone, D, Richards, AL, Rutten, BP, St Clair, D, Therman, S, Toulopoulou, T, Van Os, J, Waddington, JL, Sullivan, P, Vassos, E, Breen, G, Collier, DA, Murray, RM, Schalkwyk, LS, Mill, J, CRESTAR Consortium & Wellcome Trust Case Control Consortium (WTCCC) 2021, 'DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia', Elife, vol. 10, e58430. https://doi.org/10.7554/eLife.58430

TY - JOUR

T1 - DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

AU - Hannon, E.

AU - Dempster, E.L.

AU - Mansell, G.

AU - Burrage, J.

AU - Bass, N.

AU - Bohlken, M.M.

AU - Corvin, A.

AU - Curtis, C.J.

AU - Dempster, D.

AU - Di Forti, M.

AU - Dinan, T.G.

AU - Donohoe, G.

AU - Gaughran, F.

AU - Gill, M.

AU - Gillespie, A.

AU - Gunasinghe, C.

AU - Hulshoff, H.E.

AU - Hultman, C.M.

AU - Johansson, V.

AU - Kahn, R.S.

AU - Kaprio, J.

AU - Kenis, G.

AU - Kowalec, K.

AU - MacCabe, J.

AU - McDonald, C.

AU - McQuillin, A.

AU - Morris, D.W.

AU - Murphy, K.C.

AU - Mustard, C.J.

AU - Nenadic, I.

AU - O'Donovan, M.C.

AU - Quattrone, D.

AU - Richards, A.L.

AU - Rutten, B.P.

AU - St Clair, D.

AU - Therman, S.

AU - Toulopoulou, T.

AU - Van Os, J.

AU - Waddington, J.L.

AU - Sullivan, P.

AU - Vassos, E.

AU - Breen, G.

AU - Collier, D.A.

AU - Murray, R.M.

AU - Schalkwyk, L.S.

AU - Mill, J.

AU - CRESTAR Consortium

AU - Wellcome Trust Case Control Consortium (WTCCC)

PY - 2021/2/26

Y1 - 2021/2/26

N2 - We performed a systematic analysis of blood DNA methylation profiles from 4483 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 1048 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.

AB - We performed a systematic analysis of blood DNA methylation profiles from 4483 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 1048 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.

KW - 1ST-EPISODE PSYCHOSIS

KW - BLOOD

KW - BURDEN

KW - DISEASE

KW - HIGH-POTENCY CANNABIS

KW - HUMAN BRAIN-TISSUE

KW - METHYLOMIC VARIATION

KW - RISK

KW - TRAIT

KW - WIDE ASSOCIATION

U2 - 10.7554/eLife.58430

DO - 10.7554/eLife.58430

M3 - Article

C2 - 33646943

SN - 2050-084X

VL - 10

JO - Elife

JF - Elife

M1 - e58430

ER -