Epigenetic Marks as Peripheral Biomarkers of Autism

描述(由申请人提供)：自闭症谱系障碍(ASD)是一种常见的表型，病因复杂。虽然罕见的单个基因或基因组间隔可能足以导致ASD，但大多数患者可能将他们的疾病归因于遗传和环境变异的组合。连接遗传和环境影响的一个领域是表观遗传变异。为了寻找ASD特有的表观遗传变异的证据，我们筛查了49名ASD男性及其未受影响的父亲与807个基因对应的1,505个CpG二核苷酸的甲基化状态。使用33对作为训练集和16对作为验证集，我们统计地识别了116个差异甲基化基因座(DML)，这些DML对ASD男孩和他们的父亲的分类具有最高的预测能力。使用这些DML，我们以盲法从另外29对ASD儿子/未受影响的父亲对的全血中分离出DNA，并正确地对大约80%的ASD患者进行了分类。我们使用亚硫酸氢盐测序验证了这些基因座的一个子集，并排除了年龄相关的影响。为了跟进这一不寻常的观察，我们建议在这里进行一项全面的全基因组甲基化分析，询问从300个ASD Simons Simplex四人家庭(父亲、母亲和不和谐的男性兄弟姐妹)的全血DNA中分离出的27,578个CpG二核苷酸和超过14,000个基因。使用这些数据，我们将构建一个更小的定制DML集，并筛选另外900名ASD先证者及其家庭。这项分析将直接测试我们具有挑衅性的初步数据，并可能识别可能危及ASD外周生物标记物检测的DML。 与公共卫生相关：自闭症是一种常见的疾病，其原因尚不清楚。基因和环境的影响被认为共同作用，导致自闭症。表观遗传学是连接遗传和环境影响的一个领域，通常通过检测DNA的动态甲基化变化来研究。我们已经用这种方法在807个基因中对78名自闭症男孩和他们的父亲进行了筛查，发现116个甲基化变化加在一起可以正确识别近80%的受影响男孩和他们的父亲。我们建议在1200名自闭症男孩及其家人的一组更大的基因中证实这些令人兴奋的数据，其中包括未受影响的兄弟。这些数据不仅可以为自闭症的病因提供新的见解，还可能导致对自闭症的筛查测试。)

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) are a common phenotype with a complex etiology. While a rare single gene or genomic interval may be sufficient to lead to ASD, most patients likely owe their disease to a combination of both genetic and environmental variation. One area that bridges genetic and environmental influences is epigenetic variation. Seeking evidence for epigenetic variation specific to ASD, we screened 49 ASD males and their unaffected fathers for methylation status of 1,505 CpG dinucleotides corresponding to 807 genes. Using 33 pairs as a training set and 16 pairs as a validation set, we statistically identified 116 differentially methylated loci (DML) that gave the highest predictive power to classify ASD boys from their fathers. Using these DML, we screened, in a blinded fashion, DNA isolated from whole blood in an additional 29 ASD son/unaffected father pairs and correctly classified ~80% of the ASD affected individuals. We validated a subset of these loci using bisulfite sequencing and ruled out age-dependent effects. To follow-up on this extraordinary observation, we propose here to conduct a comprehensive genome-wide methylation analysis that will interrogate 27,578 CpG dinucleotides associated with more than 14,000 genes in DNA isolated from whole blood in 300 ASD Simons Simplex 4-person families (father, mother and discordant male sib pair). Using this data, we will then construct a smaller custom set of DML and screen an additional 900 ASD probands and their families. This analysis will directly test our provocative preliminary data and potentially identify DML that could compromise a peripheral biomarker assay for ASD. PUBLIC HEALTH RELEVANCE: Autism is a common disorder whose causes are poorly understood. Both genetic and environmental influences are thought to act together causing autism. Epigenetics is an area that bridges genetic and environmental influencing and commonly is studied by examining dynamic methylation changes to the DNA. We have screened a total of 78 autistic boys and their fathers by this method in 807 genes and find 116 methylation changes that together can correctly identify nearly 80% of the affected boys from their fathers. We propose to confirm these exciting data in a much larger set of genes in 1,200 autistic boys and their families, including unaffected brothers. These data not only could provide new insight into the causes of autism but could also result in a screening test for autism. )