PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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 (n pooled=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.
UNASSIGNED: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), 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 FDFT1 and MFHAS1), 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.
UNASSIGNED: 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.
UNASSIGNED: HorizonEurope; European Research Council.
UNASSIGNED: 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 (n pooled=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.
UNASSIGNED: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), 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 FDFT1 and MFHAS1), 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.
UNASSIGNED: 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.
UNASSIGNED: HorizonEurope; European Research Council.
摘要：
■自闭症谱系障碍（ASD），注意缺陷/多动障碍（ADHD），和精神分裂症（SCZ）是高度遗传性的，并与胎儿（神经）发育的中断有关。虽然表观遗传过程被认为是遗传易感性和神经发育状况之间的重要潜在途径，目前尚不清楚（i）对这些疾病的遗传易感性是否与表观遗传模式有关，特别是DNA甲基化（DNAm），已经出生；(Ii)DNAm模式在多大程度上是独特的或在不同条件下共享的，和（iii）是否可以利用这些新生儿DNAm模式来增强（神经）发育结局的遗传预测。
■我们对ASD的遗传易感性进行了全表观基因组荟萃分析，多动症,和精神分裂症，使用脐带血DNAm的多基因评分（PGSs）进行量化，使用四个基于人群的队列(n=5,802)，所有北欧人。异质性统计用于估计PGS之间DNAm模式的重叠。随后，基于DNAM的PGS测量是在目标样本中建立的，并用作预测因子，以检验在出生至14年的130（神经）发育结局中PGS解释的增量方差。
■在探针级分析中，SCZ-PGS与新生儿DNAm在246个基因座相关(p<9×10-8)，主要在主要的组织相容性复合体中。这些DNAm基因座的功能表征证实了强烈的遗传效应，显著的血脑一致性和免疫相关途径的富集。确定了ASD-PGS的8个基因座（定位为FDFT1和MFHAS1），ADHD-PGS没有。区域分析表明，所有PGS都存在大量差异甲基化区域（SCZ-PGS：157，ASD-PGS：130，ADHD-PGS：166）。DNAm信号显示PGS之间几乎没有重叠。我们发现了暗示性证据，表明结合基于DNAm的出生遗传易感性测量会增加PGS以上几种儿童认知和运动结果的差异。
■神经发育疾病的遗传易感性，特别是精神分裂症，在基于人群的样本中，在出生时的脐带血DNAm中可以检测到，PGS之间具有很大程度上不同的DNAM模式。这些发现支持精神分裂症的早期起源观点。
■欧洲；欧洲研究理事会。
■
■我们对ASD的遗传易感性进行了全表观基因组荟萃分析，多动症,和精神分裂症，使用脐带血DNAm的多基因评分（PGSs）进行量化，使用四个基于人群的队列(n=5,802)，所有北欧人。异质性统计用于估计PGS之间DNAm模式的重叠。随后，基于DNAM的PGS测量是在目标样本中建立的，并用作预测因子，以检验在出生至14年的130（神经）发育结局中PGS解释的增量方差。
■在探针级分析中，SCZ-PGS与新生儿DNAm在246个基因座相关(p<9×10-8)，主要在主要的组织相容性复合体中。这些DNAm基因座的功能表征证实了强烈的遗传效应，显著的血脑一致性和免疫相关途径的富集。确定了ASD-PGS的8个基因座（定位为FDFT1和MFHAS1），ADHD-PGS没有。区域分析表明，所有PGS都存在大量差异甲基化区域（SCZ-PGS：157，ASD-PGS：130，ADHD-PGS：166）。DNAm信号显示PGS之间几乎没有重叠。我们发现了暗示性证据，表明结合基于DNAm的出生遗传易感性测量会增加PGS以上几种儿童认知和运动结果的差异。
■神经发育疾病的遗传易感性，特别是精神分裂症，在基于人群的样本中，在出生时的脐带血DNAm中可以检测到，PGS之间具有很大程度上不同的DNAM模式。这些发现支持精神分裂症的早期起源观点。
■欧洲；欧洲研究理事会。
■
