DNA methylation at birth and fine motor ability in childhood: an epigenome-wide association study with replication

Lower fine motor performance in childhood has been associated with poorer cognitive development and neurodevelopmental conditions such as autism spectrum disorder, yet, biological underpinnings remain unclear. DNA methylation (DNAm), an essential process for healthy neurodevelopment, is a key molecular system of interest. In this study, we conducted the first epigenome-wide association study of neonatal DNAm with childhood fine motor ability and further examined the replicability of epigenetic markers in an independent cohort. The discovery study was embedded in Generation R, a large population-based prospective cohort, including a subsample of 924 ~ 1026 European-ancestry singletons with available data on DNAm in cord blood and fine motor ability at a mean (SD) age of 9.8 (0.4) years. Fine motor ability was measured using a finger-tapping test (3 subtests including left-, right-hand and bimanual), one of the most frequently used neuropsychological instruments of fine motor function. The replication study comprised 326 children with a mean (SD) age of 6.8 (0.4) years from an independent cohort, the INfancia Medio Ambiente (INMA) study. Four CpG sites at birth were prospectively associated with childhood fine motor ability after genome-wide correction. Of these, one CpG (cg07783800 in GNG4) was replicated in INMA, showing that lower levels of methylation at this site were associated with lower fine motor performance in both cohorts. GNG4 is highly expressed in the brain and has been implicated in cognitive decline. Our findings support a prospective, reproducible association between DNAm at birth and fine motor ability in childhood, pointing to GNG4 methylation at birth as a potential biomarker of fine motor ability.

儿童期精细运动功能低下与认知发育迟缓及自闭症谱系障碍等神经发育疾病存在关联，但其生物学基础仍未明确。DNA甲基化（DNA methylation, DNAm）是健康神经发育的关键过程，也是本研究重点关注的核心分子系统。本研究首次开展了新生儿DNA甲基化与儿童精细运动能力的全表观基因组关联研究，并在独立队列中验证了表观遗传标记的可重复性。本研究的发现队列嵌入于大型人群前瞻性队列Generation R，纳入924至1026名欧洲血统单胎婴儿的子样本，所有研究对象均具备脐带血DNA甲基化数据，且在平均年龄9.8（标准差0.4）岁时完成了精细运动能力评估。精细运动能力采用手指敲击测试进行测评，该测试包含左手、右手及双手协同三项子任务，是目前最常用的精细运动功能神经心理学评估工具之一。本研究的验证队列纳入来自独立队列INfancia Medio Ambiente（INMA）研究的326名儿童，其平均测评年龄为6.8（标准差0.4）岁。经全基因组校正后，共有4个出生时的CpG位点与儿童精细运动能力呈现前瞻性关联。其中位于GNG4基因的cg07783800位点在INMA队列中得到了重复验证，结果显示该位点较低的甲基化水平在两个队列中均与更差的精细运动表现相关。GNG4在大脑中高表达，且既往研究提示其与认知衰退存在关联。本研究结果证实了新生儿出生时的DNA甲基化水平与儿童期精细运动能力之间存在前瞻性且可重复的关联，提示出生时GNG4基因的甲基化水平可作为精细运动能力的潜在生物标志物。