Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

Joana Viana; Eilis Hannon; Emma Dempster; Ruth Pidsley; Ruby Macdonald; Olivia Knox; Helen Spiers; Claire Troakes; Safa Al-Saraj; Gustavo Turecki; Leonard C. Schalkwyk; Jonathan Mill

doi:10.1093/hmg/ddw373

Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

Joana Viana, Eilis Hannon, Emma Dempster, Ruth Pidsley, Ruby Macdonald, Olivia Knox, Helen Spiers, Claire Troakes, Safa Al-Saraj, Gustavo Turecki, Leonard C. Schalkwyk, Jonathan Mill

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

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Abstract

Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease.

Original language	English
Pages (from-to)	210-225
Number of pages	16
Journal	Human Molecular Genetics
Volume	26
Issue number	1
DOIs	https://doi.org/10.1093/hmg/ddw373
Publication status	Published - 1 Jan 2017

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Viana, J., Hannon, E., Dempster, E., Pidsley, R., Macdonald, R., Knox, O., Spiers, H., Troakes, C., Al-Saraj, S., Turecki, G., Schalkwyk, L. C., & Mill, J. (2017). Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions. Human Molecular Genetics, 26(1), 210-225. https://doi.org/10.1093/hmg/ddw373

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abstract = "Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease.",

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Viana, J, Hannon, E, Dempster, E, Pidsley, R, Macdonald, R, Knox, O, Spiers, H , Troakes, C, Al-Saraj, S, Turecki, G, Schalkwyk, LC & Mill, J 2017, 'Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions', Human Molecular Genetics, vol. 26, no. 1, pp. 210-225. https://doi.org/10.1093/hmg/ddw373

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AU - Troakes, Claire

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Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions

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