An integrated genetic-epigenetic analysis of schizophrenia : evidence for co-localization of genetic associations and differential DNA methylation

Show full item record



Permalink

http://hdl.handle.net/10138/167919

Citation

Hannon , E , Dempster , E , Viana , J , Burrage , J , Smith , A R , Macdonald , R , St Clair , D , Mustard , C , Breen , G , Therman , S , Kaprio , J , Toulopoulou , T , Pol , H E H , Bohlken , M M , Kahn , R S , Nenadic , I , Hultman , C M , Murray , R M , Collier , D A , Bass , N , Gurling , H , McQuillin , A , Schalkwyk , L & Mill , J 2016 , ' An integrated genetic-epigenetic analysis of schizophrenia : evidence for co-localization of genetic associations and differential DNA methylation ' , Genome Biology , vol. 17 , 176 . https://doi.org/10.1186/s13059-016-1041-x

Title: An integrated genetic-epigenetic analysis of schizophrenia : evidence for co-localization of genetic associations and differential DNA methylation
Author: Hannon, Eilis; Dempster, Emma; Viana, Joana; Burrage, Joe; Smith, Adam R.; Macdonald, Ruby; St Clair, David; Mustard, Colette; Breen, Gerome; Therman, Sebastian; Kaprio, Jaakko; Toulopoulou, Timothea; Pol, Hilleke E. Hulshoff; Bohlken, Marc M.; Kahn, Rene S.; Nenadic, Igor; Hultman, Christina M.; Murray, Robin M.; Collier, David A.; Bass, Nick; Gurling, Hugh; McQuillin, Andrew; Schalkwyk, Leonard; Mill, Jonathan
Contributor: University of Helsinki, Clinicum
Date: 2016-08-30
Language: eng
Number of pages: 16
Belongs to series: Genome Biology
ISSN: 1474-760X
URI: http://hdl.handle.net/10138/167919
Abstract: Background: Schizophrenia is a highly heritable, neuropsychiatric disorder characterized by episodic psychosis and altered cognitive function. Despite success in identifying genetic variants associated with schizophrenia, there remains uncertainty about the causal genes involved in disease pathogenesis and how their function is regulated. Results: We performed a multi-stage epigenome-wide association study, quantifying genome-wide patterns of DNA methylation in a total of 1714 individuals from three independent sample cohorts. We have identified multiple differentially methylated positions and regions consistently associated with schizophrenia across the three cohorts; these effects are independent of important confounders such as smoking. We also show that epigenetic variation at multiple loci across the genome contributes to the polygenic nature of schizophrenia. Finally, we show how DNA methylation quantitative trait loci in combination with Bayesian co-localization analyses can be used to annotate extended genomic regions nominated by studies of schizophrenia, and to identify potential regulatory variation causally involved in disease. Conclusions: This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.
Subject: Schizophrenia
DNA methylation
Epigenetics
Genetics
Polygenic risk score (PRS)
Genome-wide association study (GWAS)
Epigenome-wide association study (EWAS)
GENOME-WIDE ASSOCIATION
HUMAN BRAIN-TISSUE
CELL-TYPES
GENOTYPE IMPUTATION
DISEASE
RISK
BLOOD
LOCI
INFECTION
DISORDER
3111 Biomedicine
3142 Public health care science, environmental and occupational health
3124 Neurology and psychiatry
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
art_3A10.1186_2Fs13059_016_1041_x.pdf 2.172Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record