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 Pidsley2,3, Joe Burrage1, Therese M Murphy1, Claire Troakes2, Gustavo Turecki5, Michael C. O'Donovan4, Leonard C. Schalkwyk6, Nicholas J. Bray2,4, Jonathan Mill1,2

  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.

Schematic of mQTLs in genomic region: 1:2322054-2452501, making plot


If approporiate the top of the figure is the gene track, where each gene is located on a separate line with the thicker black bars indicating exons. Each gene is annotannotated with it's Entrez ID, and the red arrows indicate the direction of transcription. Vertical blue lines indicate locations of all variants tested and vertical red lines indicate locations of all DNA methylation probes tested. Significant mQTLs (P < 3.60 x 10-13) are indicated by black lines between the respective variant and DNA methylation probe, where the line width reflects the magnitude of the effect.

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Additional files

Imputed set of mQTLs

[ csv file, 13M ]

Overlap of imputed set of mQTLs and PGC2 schizophrenia GWAS variants

[ csv file, 93K ]

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

[ xslx file 4.9M ]

R Scripts

[ text files, 9.0K ]

Schizophrenia GWAS region plots


[ pdf file 8K ]


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