title: A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score.
abstract: Genome-wide association studies have identified a number of single-nucleotide polymorphisms (SNPs) that are associated with psychiatric diseases. Increasing body of evidence suggests a complex connection of SNPs and the transcriptional and epigenetic regulation of gene expression, which is poorly understood. In the current study, we investigated the interplay between genetic risk variants, shifts in methylation and mRNA levels in whole blood from 223 adolescents distinguished by a risk for developing psychiatric disorders. We analyzed 37 SNPs previously associated with psychiatric diseases in relation to genome-wide DNA methylation levels using linear models, with Bonferroni correction and adjusting for cell-type composition. Associations between DNA methylation, mRNA levels and psychiatric disease risk evaluated by the Development and Well-Being Assessment (DAWBA) score were identified by robust linear models, Pearson's correlations and binary regression models. We detected five SNPs (in HCRTR1, GAD1, HADC3 and FKBP5) that were associated with eight CpG sites, validating five of these SNP-CpG pairs. Three of these CpG sites, that is, cg01089319 (GAD1), cg01089249 (GAD1) and cg24137543 (DIAPH1), manifest in significant gene expression changes and overlap with active regulatory regions in chromatin states of brain tissues. Importantly, methylation levels at cg01089319 were associated with the DAWBA score in the discovery group. These results show how distinct SNPs linked with psychiatric diseases are associated with epigenetic shifts with relevance for gene expression. Our findings give a novel insight on how genetic variants may modulate risks for the development of psychiatric diseases.
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: D M
authors.initials: DM
authors.lastname: Ciuculete
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: A E
authors.initials: AE
authors.lastname: Boström
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Voisin
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Philipps
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: O E
authors.initials: OE
authors.lastname: Titova
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: M
authors.identifier: 0000-0002-7071-9067
authors.initials: M
authors.lastname: Bandstein
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Nikontovic
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: M J
authors.initials: MJ
authors.lastname: Williams
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Mwinyi
authors.affiliation: Division of Functional Pharmacology, Department of Neuroscience, Biomedicinskt Centrum, Uppsala University, Uppsala, Sweden.
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D019175:DNA Methylation; D005260:Female; D000080865:Formins; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000235:genetics*; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D064446:Orexin Receptors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000378:metabolism*; D012306:Risk; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5; D000099186:Histone Deacetylase 3
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000080865:Formins; D005968:Glutamate Decarboxylase; D006655:Histone Deacetylases; D064446:Orexin Receptors; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; D000099186:Histone Deacetylase 3; C108962:DIAPH1 protein, human; C578630:HCRTR1 protein, human; C402565:glutamate decarboxylase 1