期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 98, 期 5, 页码 956-962出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2016.03.006
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [MOP-199170, MOP-119451, MOP-77689]
- NIH [MH088413, DK085698]
- Krembil Foundation
- Brain Canada
- Ontario Government
- Centre for Addiction and Mental Health (CAMH) Foundation
- Joanne Murphy Professorship in Behavioural Science
- Peterborough K.M. Hunter Graduate Studentship
- Armstrong family via the CAMH Foundation
- CIHR STAGE (Strategic Training for Advanced Genetic Epidemiology) Training Grant in Genetic Epidemiology and Statistical Genetics [GET-101831]
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.
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