DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.
DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.
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DOI：
10.1038/tp.2016.247
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发表时间：
2016-12-06
影响因子：
6.8
通讯作者：
Barker ED
中科院分区：
文献类型：
--
作者：
Cecil CA;Walton E;Smith RG;Viding E;McCrory EJ;Relton CL;Suderman M;Pingault JB;McArdle W;Gaunt TR;Mill J;Barker ED
表观遗传过程与成瘾有关;然而，尚不清楚这些是否代表了一个风险因素和/或物质使用的后果。在这里，我们相信我们进行了第一个全基因组的纵向研究，以调查早期生命中的DNA甲基化模式是否与青春期的物质使用有关。样本包括来自雅芳父母和儿童纵向研究（ALSPAC）的244名青年（51%为女性），重复评估DNA甲基化（Illumina 450 k阵列;出生时的脐带血，7岁时的全血）和物质使用（烟草，酒精和大麻使用;年龄14-18）。我们发现，在出生时，在一个紧密相连的遗传网络（n=65个位点; q<0.05）中的表观遗传变异与青春期更高水平的物质使用以及使用者更早的发病年龄相关。相关性是新生儿期特有的，在7岁时没有观察到。关键的注释基因包括PACSIN 1，NEUROD 4和NTRK 2，涉及神经发育过程。几个已鉴定的基因座与已知的甲基化数量性状基因座相关，因此可能受到显著的遗传控制。总的来说，这65个位点也被发现部分介导产前母亲吸烟对青少年物质使用的影响。总之，研究结果为物质使用的表观遗传相关性提供了新的见解，突出了出生作为生物脆弱性的潜在敏感窗口，并提供了将产前烟草暴露与青少年物质使用联系起来的间接表观遗传途径的初步证据。
Epigenetic processes have been implicated in addiction; yet, it remains unclear whether these represent a risk factor and/or a consequence of substance use. Here, we believe we conducted the first genome-wide, longitudinal study to investigate whether DNA methylation patterns in early life prospectively associate with substance use in adolescence. The sample comprised of 244 youth (51% female) from the Avon Longitudinal Study of Parents and Children (ALSPAC), with repeated assessments of DNA methylation (Illumina 450k array; cord blood at birth, whole blood at age 7) and substance use (tobacco, alcohol and cannabis use; age 14–18). We found that, at birth, epigenetic variation across a tightly interconnected genetic network (n=65 loci; q<0.05) associated with greater levels of substance use during adolescence, as well as an earlier age of onset amongst users. Associations were specific to the neonatal period and not observed at age 7. Key annotated genes included PACSIN1, NEUROD4 and NTRK2, implicated in neurodevelopmental processes. Several of the identified loci were associated with known methylation quantitative trait loci, and consequently likely to be under significant genetic control. Collectively, these 65 loci were also found to partially mediate the effect of prenatal maternal tobacco smoking on adolescent substance use. Together, findings lend novel insights into epigenetic correlates of substance use, highlight birth as a potentially sensitive window of biological vulnerability and provide preliminary evidence of an indirect epigenetic pathway linking prenatal tobacco exposure and adolescent substance use.