Common DNA methylation alterations in multiple brain regions in autism

被引:230
作者
Ladd-Acosta, C. [1 ,2 ]
Hansen, K. D. [2 ,3 ,4 ]
Briem, E. [2 ,5 ]
Fallin, M. D. [1 ,2 ]
Kaufmann, W. E. [6 ]
Feinberg, A. P. [2 ,5 ]
机构
[1] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
[2] Johns Hopkins Sch Med, Inst Basic Biomed Sci, Ctr Epigenet, Baltimore, MD 21205 USA
[3] Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD USA
[4] Johns Hopkins Sch Publ Hlth, Inst Med Genet, Baltimore, MD USA
[5] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
[6] Kennedy Krieger Inst, Baltimore, MD USA
基金
美国国家卫生研究院;
关键词
autism; brain; DNA methylation; epigenome; 450; k; COPY NUMBER VARIATION; EMBRYONIC STEM-CELLS; WIDE ASSOCIATION; MUTATIONS; GENE; SPECTRUM; PRRT2; DISORDER; SHANK3; RISK;
D O I
10.1038/mp.2013.114
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485 000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.
引用
收藏
页码:862 / 871
页数:10
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