title: An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Eilis
authors: E
authors: Hannon
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Emma
authors: E
authors: Dempster
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Joana
authors: J
authors: Viana
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Joe
authors: J
authors: Burrage
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Adam R
authors: AR
authors: Smith
authors: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors: Ruby
authors: R
authors: Macdonald
authors: The Institute of Medical Sciences, Aberdeen University, Aberdeen, UK.
authors: David
authors: D
authors: St Clair
authors: University of the Highlands and Islands, Inverness, UK.
authors: Colette
authors: C
authors: Mustard
authors: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.
authors: Gerome
authors: G
authors: Breen
authors: National Institute for Health and Welfare, Helsinki, Finland.
authors: Sebastian
authors: S
authors: Therman
authors: National Institute for Health and Welfare, Helsinki, Finland.|Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.|Department of Public Health, University of Helsinki, Helsinki, Finland.
authors: Jaakko
authors: J
authors: Kaprio
authors: Department of Psychology, The University of Hong Kong, Pokfulam, Hong Kong.
authors: Timothea
authors: T
authors: Toulopoulou
authors: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Hilleke E
authors: HE
authors: Hulshoff Pol
authors: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Marc M
authors: MM
authors: Bohlken
authors: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Rene S
authors: RS
authors: Kahn
authors: Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
authors: Igor
authors: I
authors: Nenadic
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.
authors: Christina M
authors: CM
authors: Hultman
authors: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.
authors: Robin M
authors: RM
authors: Murray
authors: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.|Eli Lilly and Company Ltd, Windlesham, UK.
authors: David A
authors: DA
authors: Collier
authors: Division of Psychiatry, University College London, London, UK.
authors: Nick
authors: N
authors: Bass
authors: Division of Psychiatry, University College London, London, UK.
authors: Hugh
authors: H
authors: Gurling
authors: Division of Psychiatry, University College London, London, UK.
authors: Andrew
authors: A
authors: McQuillin
authors: Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.|School of Biological Sciences, University of Essex, Colchester, UK.
authors: Leonard
authors: L
authors: Schalkwyk
authors: University of Exeter Medical School, University of Exeter, Exeter, UK. J.Mill@exeter.ac.uk.|Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK. J.Mill@exeter.ac.uk.|Royal Devon & Exeter Hospital, RILD Building, Level 4, Barrack Rd, Exeter, EX2 5DW, UK. J.Mill@exeter.ac.uk.
authors: Jonathan
authors: J
authors: Mill
mesh_terms: D001499:Bayes Theorem; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D057890:Epigenomics; D055106:Genome-Wide Association Study; D006801:Humans; D020412:Multifactorial Inheritance / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D014430:Twins, Monozygotic
keywords: DNA methylation; Epigenetics; Epigenome-wide association study (EWAS); Genetics; Genome-wide association study (GWAS); Polygenic risk score (PRS); Schizophrenia