Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia

Ruth Pidsley, Joana Viana, Eilis Hannon, Helen Spiers, Claire Troakes, Safa Al-Sarraj, Naguib Mechawar, Gustavo Turecki, Leonard C Shalkwyk, Nicholas J Bray, Jonathan Mill

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Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances in early brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development.
We profile methylomic variation in matched prefrontal cortex and cerebellum brain tissue from schizophrenia patients and controls, identifying disease-associated differential DNA methylation at multiple loci, particularly in the prefrontal cortex, and confirming these differences in an independent set of adult brain samples. Our data reveal discrete modules of co-methylated loci associated with schizophrenia that are enriched for genes involved in neurodevelopmental processes and include loci implicated by genetic studies of the disorder. Methylomic data from human fetal cortex samples, spanning 23 to 184 days post-conception, indicates that schizophrenia-associated differentially methylated positions are significantly enriched for loci at which DNA methylation is dynamically altered during human fetal brain development.
Our data support the hypothesis that schizophrenia has an important early neurodevelopmental component, and suggest that epigenetic mechanisms may mediate these effects.
Original languageEnglish
Article number483
Number of pages10
JournalGenome Biology
Issue number10
Early online date28 Oct 2014
Publication statusPublished - 28 Oct 2014


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