Elevated polygenic burden for autism is associated with differential DNA methylation at birth.
Elevated polygenic burden for autism is associated with differential DNA methylation at birth.
复制标题
DOI：
10.1186/s13073-018-0527-4
复制
发表时间：
2018-03-28
期刊：
影响因子：
12.3
通讯作者：
Mill J
中科院分区：
文献类型：
--
作者：
Hannon E;Schendel D;Ladd-Acosta C;Grove J;iPSYCH-Broad ASD Group;Hansen CS;Andrews SV;Hougaard DM;Bresnahan M;Mors O;Hollegaard MV;Bækvad-Hansen M;Hornig M;Mortensen PB;Børglum AD;Werge T;Pedersen MG;Nordentoft M;Buxbaum J;Daniele Fallin M;Bybjerg-Grauholm J;Reichenberg A;Mill J
自闭症谱系障碍（ASD）是一种严重的神经发育障碍，其特征是社会沟通缺陷和限制、重复的行为、兴趣或活动。ASD的病因学涉及遗传和环境风险因素，表观遗传过程被假设为遗传和非遗传变异影响基因调控和发病的一种机制。本研究的目的是鉴定出生时可检测到的ASD的DNA甲基化生物标志物。我们对1263名婴儿（其中约50%随后发展为自闭症）的新生儿甲基组变异进行了量化，使用的DNA是从出生后不久采集的存档血斑中分离出来的。我们使用来自相同个体的匹配基因型数据来检查ASD相关遗传风险变异的分子后果，确定与ASD多基因负担升高相关的甲基组变异。此外，我们进行了DNA甲基化定量性状位点（mQTL）定位，以优先考虑ASD GWAS发现的靶基因。我们确定了胎龄和产前烟草暴露的强大表观遗传特征，证实了新生儿血斑产生的DNA甲基化数据的实用性。虽然我们没有发现新生儿DNA甲基化与后期ASD相关的特异性位点，但自闭症多基因负担的增加与特定位点的甲基化变异之间存在显著关联。ASD多基因风险评分每升高一个单位，与8号染色体上ASD的强大GWAS信号附近的两个CpG位点的DNA甲基化平均增加- 0.14%相关。这项研究是对ASD中DNA甲基化进行的最大规模的分析，也是第一次整合出生时的遗传和表观遗传变异。我们展示了使用多基因风险评分来识别与疾病相关的分子变异的实用性，以及使用mQTL来完善与ASD风险变异相关的功能和调控变异的实用性。本文的在线版本（10.1186/ s130773 -018-0527-4）包含补充材料，授权用户可使用。
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. We quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants. The online version of this article (10.1186/s13073-018-0527-4) contains supplementary material, which is available to authorized users.
登录
查看更多内容
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.8
作者：
Homs A;Codina-Solà M;Rodríguez-Santiago B;Villanueva CM;Monk D;Cuscó I;Pérez-Jurado LA
通讯作者：
Pérez-Jurado LA
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
25
作者：
Hannon E;Spiers H;Viana J;Pidsley R;Burrage J;Murphy TM;Troakes C;Turecki G;O'Donovan MC;Schalkwyk LC;Bray NJ;Mill J
通讯作者：
Mill J
影响因子：
10.5
作者：
Baron-Cohen, Simon;Scott, Fiona J.;Brayne, Carol
通讯作者：
Brayne, Carol