Schuurmans I K, Smajlagic D, Baltramonaityte V, Malmberg A L K, Neumann A, Creasey N, Felix J F, Tiemeier H, Pingault J B, Czamara D, Raïkkönen K, Page C M, Lyle R, Havdahl A, Lahti J, Walton E, Bekkhus M, Cecil C A M
Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
medRxiv. 2024 Jul 1:2024.07.01.24309384. doi: 10.1101/2024.07.01.24309384.
Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes.
We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts ( =5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years.
In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to and ), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS.
Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia.
HorizonEurope; European Research Council.
自闭症谱系障碍（ASD）、注意力缺陷多动障碍（ADHD）和精神分裂症（SCZ）具有高度遗传性，且与胎儿（神经）发育紊乱有关。虽然表观遗传过程被认为是遗传易感性与神经发育状况之间的重要潜在途径，但尚不清楚：（i）这些疾病的遗传易感性是否在出生时就与表观遗传模式，特别是DNA甲基化（DNAm）相关；（ii）DNAm模式在不同疾病之间有多大程度的独特性或共享性；以及（iii）这些新生儿DNAm模式是否可用于增强对（神经）发育结局的遗传预测。
我们对ASD、ADHD和精神分裂症的遗传易感性进行了全表观基因组荟萃分析，使用基于四个北欧人群队列（n = 5802）的脐带血DNAm多基因评分（PGS）进行量化。异质性统计用于估计PGS之间DNAm模式的重叠情况。随后，在一个目标样本中构建基于DNAm的PGS测量值，并将其用作预测因子，以检验在涵盖出生至14岁的130项（神经）发育结局中，相对于PGS所解释的增量方差。
在探针水平分析中，SCZ-PGS与246个位点的新生儿DNAm相关（p < 9×10⁻⁸），主要位于主要组织相容性复合体中。这些DNAm位点的功能特征证实了强大的遗传效应、显著的血脑一致性以及免疫相关途径的富集。为ASD-PGS鉴定出8个位点（映射到……），而ADHD-PGS未鉴定出相关位点。区域分析表明，所有PGS都有大量差异甲基化区域（SCZ-PGS：157个，ASD-PGS：130个，ADHD-PGS：166个）。DNAm信号在PGS之间几乎没有重叠。我们发现有提示性证据表明，纳入出生时基于DNAm的遗传易感性测量值，相对于PGS，可增加对几个儿童认知和运动结局的解释方差。
在基于人群的样本中，出生时的脐带血DNAm可检测到神经发育疾病，特别是精神分裂症的遗传易感性，且PGS之间的DNAm模式在很大程度上是不同的。这些发现支持了精神分裂症的早期起源观点。
地平线欧洲；欧洲研究理事会。
