title: Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
abstract: We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were 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 found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Spiers
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Viana
authors.affiliation: Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Burrage
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.
authors.forename: Therese M
authors.initials: TM
authors.lastname: Murphy
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Douglas Mental Health Institute, McGill University, Montreal, QC, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Michael C
authors.identifier: http://orcid.org/0000-0001-7073-2379
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: School of Biological Sciences, University of Essex, Colchester, UK.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.|MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bray
authors.affiliation: University of Exeter Medical School, University of Exeter, Exeter, UK.|Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
mesh_terms: D000328:Adult; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005333:Fetus; D015870:Gene Expression / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D017072:Neostriatum / Q000196:embryology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000196:embryology / Q000378:metabolism; D040641:Quantitative Trait Loci / Q000235:genetics*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D014015:Tissue Banks