title: Allele-Skewed DNA Modification in the Brain: Relevance to a Schizophrenia GWAS.
abstract: Numerous recent studies have suggested that phenotypic effects of DNA sequence variants can be mediated or modulated by their epigenetic marks, such as allele-skewed DNA modification (ASM). Using Affymetrix SNP microarrays, we performed a comprehensive search of ASM effects in human post-mortem brain and sperm samples (total n = 256) from individuals with major psychosis and control individuals. Depending on the phenotypic category of the brain samples, 1.4%-7.5% of interrogated SNPs exhibited ASM effects. Next, we investigated ASM in the context of genetic studies of schizophrenia and detected that brain ASM SNPs were significantly overrepresented among sub-threshold SNPs from a schizophrenia genome-wide association study (GWAS). Brain ASM SNPs showed a much stronger enrichment in a schizophrenia GWAS than in 17 large GWASs of non-psychiatric diseases and traits, arguing that ASM effects are at least partially tissue specific. Studies of germline and control brain ASM SNPs supported a causal association between ASM and schizophrenia. Finally, significantly higher proportions of ASM SNPs than of non-ASM SNPs were detected at loci exhibiting epigenetic signatures of enhancers and promoters, and they were overrepresented within transcription factor binding regions and DNase I hypersensitive sites. All of these findings collectively indicate that ASM SNPs should be prioritized in follow-up GWASs.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Gagliano
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ptak
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada.
authors.forename: Denise Y F
authors.initials: DYF
authors.lastname: Mak
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Informatics and Biocomputing Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamsi
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Oh
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Biostatistics Division, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Knight
authors.affiliation: Informatics and Biocomputing Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: paul.boutros@oicr.on.ca.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Institute of Medical Science, University of Toronto, ON M5S 1A8, Canada; Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: art.petronis@camh.ca.
authors.forename: Arturas
authors.initials: A
authors.lastname: Petronis
mesh_terms: D000483:Alleles; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D019175:DNA Methylation; D057890:Epigenomics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*