Allele-skewed DNA modification in the brain:relevance to a schizophrenia GWAS

Gagliano, Sarah A. and Ptak, Carolyn and Mak, Denise Y. F. and Shamsi, Mehrdad and Oh, Gabriel and Knight, Joanne and Boutros, Paul C. and Petronis, Arturas (2016) Allele-skewed DNA modification in the brain:relevance to a schizophrenia GWAS. American Journal of Human Genetics, 98 (5). pp. 956-962. ISSN 0002-9297

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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.

Item Type:
Journal Article
Journal or Publication Title:
American Journal of Human Genetics
Additional Information:
This is the author’s version of a work that was accepted for publication in American Journal of Human Genetics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in American Journal of Human Genetics, 98, 5, 2016 DOI: 10.1016/j.ajhg.2016.03.006
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2716
Subjects:
ID Code:
79880
Deposited By:
Deposited On:
13 Jun 2016 08:28
Refereed?:
Yes
Published?:
Published
Last Modified:
20 Sep 2020 03:35