DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.
DNA methylation
clozapine
epigenetics
genetics
genomics
human
psychosis
schizophrenia
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
26 02 2021
26 02 2021
Historique:
received:
01
05
2020
accepted:
23
02
2021
pubmed:
2
3
2021
medline:
29
1
2022
entrez:
1
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33646943
doi: 10.7554/eLife.58430
pii: 58430
pmc: PMC8009672
doi:
pii:
Banques de données
GEO
['GSE147221', 'GSE80417', 'GSE84727']
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/R005176/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0801418
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH077139
Pays : United States
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 085475/B/08/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800509
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 072894/Z/03/Z
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH052857
Pays : United States
Organisme : Medical Research Council
ID : MR/K013807/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 075491/Z/04/B
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T007818/1
Pays : United Kingdom
Organisme : Department of Health
ID : RP-PG-0606-1049
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 090532/Z/09/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L011794/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008924/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : Fellowship (MR/M008436/1)
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 085475/Z/08/Z
Pays : United Kingdom
Informations de copyright
© 2021, Hannon et al.
Déclaration de conflit d'intérêts
EH, ED, GM, JB, NB, MB, AC, CC, DD, TD, GD, MG, AG, CG, HH, CH, VJ, RK, JK, GK, CM, AM, DM, KM, CM, IN, DQ, AR, BR, DS, ST, TT, JV, JW, EV, GB, LS, JM No competing interests declared, MD M Di Forti reports personal fees from Janssen, outside the submitted work. FG Fiona Gaughran has received honoraria from Lundbeck, Otsuka, and Sunovion. She has a family member with professional links to Lilly and GSK, including shares. KK Kaarina Kowalec has consulted with Emerald Lake Safety Ltd. (2017-2018) and has received speaker honoraria from Biogen/Fraser Health Multiple Sclerosis Clinic (2018). Both are unrelated to the work published here. JM James MacCabe has received research funding from H Lundbeck. MO Michael C O'Donovan is supported by a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study. PS PF Sullivan reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient). Past three years: Pfizer (scientific advisory board). DC David A Collier is a full time employee and stockholder of Eli Lilly and Company. RM Robin M Murray reports personal fees from Janssen, Lundbeck, Sunovion, Recordati and Otsuka
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