Simpkin Andrew J, Suderman Matthew, Gaunt Tom R, Lyttleton Oliver, McArdle Wendy L, Ring Susan M, Tilling Kate, Davey Smith George, Relton Caroline L
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol,
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol.
Hum Mol Genet. 2015 Jul 1;24(13):3752-63. doi: 10.1093/hmg/ddv119. Epub 2015 Apr 13.
Gestational age (GA) and birth weight have been implicated in the determination of long-term health. It has been hypothesized that changes in DNA methylation may mediate these long-term effects. We obtained DNA methylation profiles from cord blood and peripheral blood at ages 7 and 17 in the same children from the Avon Longitudinal Study of Parents and Children. Repeated-measures data were used to investigate changes in birth-related methylation during childhood and adolescence. Ten developmental phenotypes (e.g. height) were analysed to identify possible mediation of health effects by DNA methylation. In cord blood, methylation at 224 CpG sites was found to be associated with GA and 23 CpG sites with birth weight. Methylation changed in the majority of these sites over time, but neither birth characteristic was strongly associated with methylation at age 7 or 17 (using a conservative correction for multiple testing of P < 1.03 × 10(-7)), suggesting resolution of differential methylation by early childhood. Associations were observed between birth weight-associated CpG sites and phenotypic characteristics in childhood. One strong association involved birth weight, methylation of a CpG site proximal to the NFIX locus and bone mineral density at age 17. Analysis of serial methylation from birth to adolescence provided evidence for a lack of persistence of methylation differences beyond early childhood. Sites associated with birth weight were linked to developmental genes and have methylation levels which are associated with developmental phenotypes. Replication and interrogation of causal relationships are needed to substantiate whether methylation differences at birth influence the association between birth weight and development.
孕周（GA）和出生体重与长期健康状况的确定有关。据推测，DNA甲基化的变化可能介导这些长期影响。我们从雅芳亲子纵向研究中同一批儿童的脐带血和7岁及17岁时的外周血中获取了DNA甲基化图谱。采用重复测量数据来研究儿童期和青少年期与出生相关的甲基化变化。分析了十种发育表型（如身高），以确定DNA甲基化对健康影响的可能介导作用。在脐带血中，发现224个CpG位点的甲基化与孕周相关，23个CpG位点的甲基化与出生体重相关。随着时间的推移，这些位点中的大多数甲基化发生了变化，但在7岁或17岁时，这两种出生特征与甲基化均无强烈关联（采用保守的多重检验校正，P<1.03×10⁻⁷），这表明儿童早期差异甲基化得到了解决。观察到出生体重相关的CpG位点与儿童期表型特征之间存在关联。一个强烈的关联涉及出生体重、NFIX基因座附近一个CpG位点的甲基化以及17岁时的骨矿物质密度。对从出生到青少年期的连续甲基化分析提供了证据，表明儿童早期之后甲基化差异缺乏持续性。与出生体重相关的位点与发育基因相关，其甲基化水平与发育表型相关。需要对因果关系进行重复验证和探究，以证实出生时的甲基化差异是否会影响出生体重与发育之间的关联。
