Methylation quantitative trait loci (mQTL) in the developing human brain and their enrichment in genomic regions associated with schizophrenia.

Eilis Hannon¹, Helen Spiers², Joana Viana¹, Ruth Pidsley^2,3, Joe Burrage¹, Therese M Murphy¹, Claire Troakes², Gustavo Turecki⁵, Michael C. O'Donovan⁴, Leonard C. Schalkwyk⁶, Nicholas J. Bray^2,4, Jonathan Mill^1,2

1. University of Exeter Medical School, University of Exeter, Exeter, UK
2. Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
3. Garvan Institute of Medical Research, Sydney 2010, NSW, Australia
4. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff UK
5. Douglas Mental Health Institute, McGill University, Montreal, QC, Canada
6. School of Biological Sciences, University of Essex, Colchester, UK

We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n=166) of human fetal brain samples spanning 56-166 days post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs are primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and show significant overlap with genetic variants also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum) we show that most fetal brain mQTLs are developmentally stable, although a subset is characterized by fetal-specific effects. We show that fetal brain mQTLs are enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we demonstrate how mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.

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cg07900658

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cg07900658

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Enter genomic region in format chr:start-end

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Additional files

Imputed set of mQTLs

Overlap of imputed set of mQTLs and PGC2 schizophrenia GWAS variants

Overlap of imputed set of mQTLs and eQTLs from Ramasamy et al 2014.

R Scripts

Schizophrenia GWAS region plots

chr1:2322054-2452501

chr3:52491105-52953405

chr5:139973664-140272664

chr7:1846096-2240096

chr12:29905265-29940365

chr12:123448113-123909113

chr15:78803032-78926732

chr17:17722402-18030202

chr19:19324022-19708022