Format

Send to

Choose Destination
Genome Biol. 2016 Aug 30;17(1):176. doi: 10.1186/s13059-016-1041-x.

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

Author information

1
University of Exeter Medical School, University of Exeter, Exeter, UK.
2
The Institute of Medical Sciences, Aberdeen University, Aberdeen, UK.
3
University of the Highlands and Islands, Inverness, UK.
4
Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.
5
National Institute for Health and Welfare, Helsinki, Finland.
6
Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
7
Department of Public Health, University of Helsinki, Helsinki, Finland.
8
Department of Psychology, The University of Hong Kong, Pokfulam, Hong Kong.
9
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
10
Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
11
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
12
Eli Lilly and Company Ltd, Windlesham, UK.
13
Division of Psychiatry, University College London, London, UK.
14
School of Biological Sciences, University of Essex, Colchester, UK.
15
University of Exeter Medical School, University of Exeter, Exeter, UK. J.Mill@exeter.ac.uk.
16
Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK. J.Mill@exeter.ac.uk.
17
Royal Devon & Exeter Hospital, RILD Building, Level 4, Barrack Rd, Exeter, EX2 5DW, UK. J.Mill@exeter.ac.uk.

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.

KEYWORDS:

DNA methylation; Epigenetics; Epigenome-wide association study (EWAS); Genetics; Genome-wide association study (GWAS); Polygenic risk score (PRS); Schizophrenia

PMID:
27572077
PMCID:
PMC5004279
DOI:
10.1186/s13059-016-1041-x
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center