Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
J Child Psychol Psychiatry. 2024 Jan;65(1):77-90. doi: 10.1111/jcpp.13866. Epub 2023 Jul 19.
Lateral ventricular volume (LVV) enlargement has been repeatedly linked to schizophrenia; yet, what biological factors shape LVV during early development remain unclear. DNA methylation (DNAm), an essential process for neurodevelopment that is altered in schizophrenia, is a key molecular system of interest.
In this study, we conducted the first epigenome-wide association study of neonatal DNAm in cord blood with LVV in childhood (measured using T1-weighted brain scans at 10 years), based on data from a large population-based birth cohort, the Generation R Study (N = 840). Employing both probe-level and methylation profile score (MPS) approaches, we further examined whether epigenetic modifications identified at birth in cord blood are: (a) also observed cross-sectionally in childhood using peripheral blood DNAm at age of 10 years (Generation R, N = 370) and (b) prospectively associated with LVV measured in young adulthood in an all-male sample from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 114).
At birth, DNAm levels at four CpGs (annotated to potassium channel tetramerization domain containing 3, KCTD3; SHH signaling and ciliogenesis regulator, SDCCAG8; glutaredoxin, GLRX) prospectively associated with childhood LVV after genome-wide correction; these genes have been implicated in brain development and psychiatric traits including schizophrenia. An MPS capturing a broader epigenetic profile of LVV - but not individual top hits - showed significant cross-sectional associations with LVV in childhood in Generation R and prospectively associated with LVV in early adulthood within ALSPAC.
This study finds suggestive evidence that DNAm at birth prospectively associates with LVV at different life stages, albeit with small effect sizes. The prediction of MPS on LVV in a childhood sample and an independent male adult sample further underscores the stability and reproducibility of DNAm as a potential marker for LVV. Future studies with larger samples and comparable time points across development are needed to further elucidate how DNAm associates with this clinically relevant brain structure and risk for neuropsychiatric disorders, and what factors explain the identified DNAm profile of LVV at birth.
侧脑室容积（LVV）扩大与精神分裂症反复相关；然而，在早期发育过程中塑造 LVV 的生物因素仍不清楚。DNA 甲基化（DNAm）是神经发育的一个重要过程，在精神分裂症中发生改变，是一个关键的分子系统。
在这项研究中，我们基于大型基于人群的出生队列——“生育研究”（Generation R Study）的数据，进行了首次新生儿脐带血 DNAm 与儿童时期 LVV 的全基因组关联研究（使用 10 岁时的 T1 加权脑扫描测量）。采用探针水平和甲基化谱评分（MPS）方法，我们进一步研究了在脐带血中出生时确定的表观遗传修饰是否：（a）在儿童时期也可以通过 10 岁时的外周血 DNAm 进行横断面研究（Generation R，N=370），以及（b）在来自阿冯纵向研究父母和儿童（ALSPAC）的全男性样本中，前瞻性地与成年早期 LVV 相关（N=114）。
在出生时，四个 CpG 位点（注释为钾通道四聚化结构域包含 3、KCTD3；SHH 信号和纤毛生成调节剂、SDCCAG8；谷氧还蛋白、GLRX）的 DNAm 水平在全基因组校正后与儿童时期的 LVV 前瞻性相关；这些基因与脑发育和包括精神分裂症在内的精神特征有关。一个捕捉 LVV 更广泛表观遗传特征的 MPS——但不是单个最高命中——在 Generation R 中显示出与儿童时期 LVV 的显著横断面关联，并在 ALSPAC 中与成年早期的 LVV 前瞻性相关。
这项研究发现了有希望的证据，表明出生时的 DNAm 与不同生命阶段的 LVV 前瞻性相关，尽管效应大小较小。MPS 在儿童样本和独立的男性成年样本中对 LVV 的预测进一步强调了 DNAm 作为 LVV 潜在标志物的稳定性和可重复性。需要更大的样本和在整个发育过程中具有可比时间点的未来研究来进一步阐明 DNAm 如何与这种临床相关的大脑结构和神经精神障碍风险相关，以及哪些因素解释了出生时 LVV 的确定 DNAm 特征。
