Early life DNA methylation patterns linking intra-uterine events to adverse cardiometabolic outcomes

生命早期 DNA 甲基化模式将子宫内事件与不良心脏代谢结果联系起来

• 批准号: MR/N015355/1
• 负责人: Alexander Drong
• 金额: $ 34.26万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN015355%2F1
• 关键词: Early; life; DNA; methylation; patterns

Complex diseases are typically caused by a mixture of genetic, environmental and epigenetic effects. A number of prenatal risk factors, including intra-uterine growth restriction (IUGR) and gestational diabetes mellitus (GDM), have been shown to determine signatures in the blood methylome. However, most studies on this topic fall short are underpowered, or fail to take genetic effects into account to investigate causality. Birth cohorts with multiple tissue samples and deep phenotyping offer an opportunity to investigate the interplay of genetics, epigenetics and the environment affecting foetal and child growth. Moreover, my project aims to specifically determine which changes in DNA methylation are causal to subsequent disease states by combining genetic and epigenetic data in Mendelian Randomization experiments. The discovered results can then be used to develop biological tools to detect children at risk stratify risk groups and develop prevention strategies. The work I propose to undertake follows on from my recent research in cross-sectional epigenome-wide association studies (EWAS) for T2D and obesity In adults (Wahl*, Drong* et al. under review). However, I have found previously that most of the strongest signals of methylations associations display a reverse causal relationship. I am thus interested to investigate the influence of early-life events, such as foetal growth and gestational diabetes (GDM) on patterns of DNA methylation. To achieve this, I aim to employ quantitative skills to develop robust methodology to take into effect confounding effects from experimental confounders (mixture of foetal/maternal tissues), maternal/paternal genotypes and to develop a robust, reusable pipeline for Mendelian Randomization in birth cohorts. Ultimately, I aim to link epigenetic markers both identified for GDM and IUGR with future health outcomes, and develop biomarkers for the effects. Firstly, I aim to apply my analysis methodology to utilise the rich data sets curated by the proposed research sponsors to detect associations of DNA methylation with a number of phenotypes. I will perform a large scale EWAS case/control studies for GDM. Secondly, I will lead for the analysis of epigenetic data from biological samples for IGUR in the INTERBIO-21 study. This includes development of the experimental designs for large-scale epigenome-wide association scans. Lastly, I will be utilizing genetic variants as instrumental variables in two-step Mendelian Randomization to determine whether epigenetic markers are in causal pathways linking intra-uterine events to the child's phenotypes. Thus I will apply an informed approach about causality to separately detect genetic associations to avoid bias and will be able to detect maternal genetic and epigenetic confounding. This will allow me to be in a unique position by extending the scope of simple cross-sectional EWAS to include not only causal analysis, but also a robust characterisation with respect to biological and technical confounders. By focussing my hypothesis on causal pathways, my work can filter out reverse-causal confounders facilitate personalised prevention and novel drug target discovery. If successful, my research will provide accurate tools to guide childhood interventions through early biomarkers of the intrauterine environment.

复杂疾病通常是由遗传、环境和表观遗传效应的混合物引起的。许多产前风险因素，包括宫内生长受限（IUGR）和妊娠期糖尿病（GDM），已被证明可以确定血液甲基化组中的签名。然而，大多数关于这一主题的研究都不够有力，或者没有考虑到遗传效应来调查因果关系。具有多个组织样本和深度表型分析的出生队列提供了一个机会，可以研究遗传学、表观遗传学和影响胎儿和儿童生长的环境之间的相互作用。此外，我的项目旨在通过结合孟德尔随机化实验中的遗传和表观遗传数据，具体确定DNA甲基化的哪些变化是导致随后疾病状态的原因。这些发现的结果可用于开发生物学工具，以检测处于危险中的儿童，对危险群体进行分层，并制定预防战略。 我建议开展的工作是我最近在成人T2 D和肥胖的横断面表观基因组关联研究（EWAS）中的研究（Wahl*，Drong* 等人正在审查）。然而，我之前已经发现，大多数甲基化关联的最强信号显示出反向因果关系。因此，我有兴趣研究生命早期事件的影响，如胎儿生长和妊娠期糖尿病（GDM）对DNA甲基化模式的影响。为了实现这一目标，我的目标是利用定量技能来开发稳健的方法，以考虑实验混杂因素（胎儿/母体组织的混合物）、母体/父亲基因型的混杂效应，并开发一个稳健的、可重复使用的孟德尔随机化管道出生队列。最终，我的目标是将GDM和IUGR的表观遗传标记与未来的健康结果联系起来，并开发生物标志物。 首先，我的目标是应用我的分析方法，利用拟议的研究赞助商策划的丰富数据集来检测DNA甲基化与许多表型的关联。我将对GDM进行大规模EWAS病例/对照研究。其次，我将在INTERBIO-21研究中负责分析IGUR生物样本的表观遗传数据。这包括开发大规模表观基因组关联扫描的实验设计。最后，我将利用遗传变异作为两步孟德尔随机化的工具变量，以确定表观遗传标记是否在将子宫内事件与儿童表型联系起来的因果通路中。因此，我将应用一种关于因果关系的知情方法来分别检测遗传关联以避免偏倚，并将能够检测母体遗传和表观遗传混淆。 这将使我处于一个独特的位置，通过扩展简单的横截面EWAS的范围，不仅包括因果分析，而且还包括生物和技术混杂因素的强大表征。通过将我的假设集中在因果通路上，我的工作可以过滤出反向因果混杂因素，促进个性化预防和新药物靶点发现。如果成功，我的研究将提供准确的工具，通过宫内环境的早期生物标志物指导儿童干预。

项目成果

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

全基因组范围的体重指数研究和肥胖的不利结果。

• DOI: 10.1038/nature20784
• 发表时间: 2017-01-05
• 期刊: Nature
• 影响因子: 64.8
• 作者: Wahl S;Drong A;Lehne B;Loh M;Scott WR;Kunze S;Tsai PC;Ried JS;Zhang W;Yang Y;Tan S;Fiorito G;Franke L;Guarrera S;Kasela S;Kriebel J;Richmond RC;Adamo M;Afzal U;Ala-Korpela M;Albetti B;Ammerpohl O;Apperley JF;Beekman M;Bertazzi PA;Black SL;Blancher C;Bonder MJ;Brosch M;Carstensen-Kirberg M;de Craen AJ;de Lusignan S;Dehghan A;Elkalaawy M;Fischer K;Franco OH;Gaunt TR;Hampe J;Hashemi M;Isaacs A;Jenkinson A;Jha S;Kato N;Krogh V;Laffan M;Meisinger C;Meitinger T;Mok ZY;Motta V;Ng HK;Nikolakopoulou Z;Nteliopoulos G;Panico S;Pervjakova N;Prokisch H;Rathmann W;Roden M;Rota F;Rozario MA;Sandling JK;Schafmayer C;Schramm K;Siebert R;Slagboom PE;Soininen P;Stolk L;Strauch K;Tai ES;Tarantini L;Thorand B;Tigchelaar EF;Tumino R;Uitterlinden AG;van Duijn C;van Meurs JB;Vineis P;Wickremasinghe AR;Wijmenga C;Yang TP;Yuan W;Zhernakova A;Batterham RL;Smith GD;Deloukas P;Heijmans BT;Herder C;Hofman A;Lindgren CM;Milani L;van der Harst P;Peters A;Illig T;Relton CL;Waldenberger M;Järvelin MR;Bollati V;Soong R;Spector TD;Scott J;McCarthy MI;Elliott P;Bell JT;Matullo G;Gieger C;Kooner JS;Grallert H;Chambers JC
• 通讯作者: Chambers JC

Variability of genome-wide DNA methylation and mRNA expression profiles in reproductive and endocrine disease related tissues.

• DOI: 10.1080/15592294.2017.1367475
• 发表时间: 2017
• 期刊: Epigenetics
• 影响因子: 3.7
• 作者: Rahmioglu N;Drong AW;Lockstone H;Tapmeier T;Hellner K;Saare M;Laisk-Podar T;Dew C;Tough E;Nicholson G;Peters M;Morris AP;Lindgren CM;Becker CM;Zondervan KT
• 通讯作者: Zondervan KT

Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation.

• DOI: 10.1038/ng.3738
• 发表时间: 2017-01
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Chu AY;Deng X;Fisher VA;Drong A;Zhang Y;Feitosa MF;Liu CT;Weeks O;Choh AC;Duan Q;Dyer TD;Eicher JD;Guo X;Heard-Costa NL;Kacprowski T;Kent JW Jr;Lange LA;Liu X;Lohman K;Lu L;Mahajan A;O'Connell JR;Parihar A;Peralta JM;Smith AV;Zhang Y;Homuth G;Kissebah AH;Kullberg J;Laqua R;Launer LJ;Nauck M;Olivier M;Peyser PA;Terry JG;Wojczynski MK;Yao J;Bielak LF;Blangero J;Borecki IB;Bowden DW;Carr JJ;Czerwinski SA;Ding J;Friedrich N;Gudnason V;Harris TB;Ingelsson E;Johnson AD;Kardia SL;Langefeld CD;Lind L;Liu Y;Mitchell BD;Morris AP;Mosley TH Jr;Rotter JI;Shuldiner AR;Towne B;Völzke H;Wallaschofski H;Wilson JG;Allison M;Lindgren CM;Goessling W;Cupples LA;Steinhauser ML;Fox CS
• 通讯作者: Fox CS