Isabel K Schuurmans, Dinka Smajlagic, Vilte Baltramonaityte, Anni L K Malmberg, Alexander Neumann, Nicole Creasey, Janine F Felix, Henning Tiemeier, Jean-Baptiste Pingault, Darina Czamara, Katri Raïkkönen, Chistian Magnus Page, Robert Lyle, Alexandra Havdahl, Jari Lahti, Esther Walton, Mona Bekkhus, Charlotte A M Cecil
{"title":"一般人群中与新生儿DNA甲基化模式相关的神经发育状况的遗传易感性：个体参与者数据荟萃分析","authors":"Isabel K Schuurmans, Dinka Smajlagic, Vilte Baltramonaityte, Anni L K Malmberg, Alexander Neumann, Nicole Creasey, Janine F Felix, Henning Tiemeier, Jean-Baptiste Pingault, Darina Czamara, Katri Raïkkönen, Chistian Magnus Page, Robert Lyle, Alexandra Havdahl, Jari Lahti, Esther Walton, Mona Bekkhus, Charlotte A M Cecil","doi":"10.1016/j.biopsych.2025.09.005","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. Yet, it is unclear whether: (i) genetic susceptibility to neurodevelopmental conditions associates with DNAm patterns already at birth; (ii) DNAm patterns are unique or shared across conditions, and (iii) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes.</p><p><strong>Methods: </strong>We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia (measured with polygenic scores [PGSs]) and cord blood DNAm in four European population-based cohorts (n<sub>pooled</sub>=5,802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Further, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years.</p><p><strong>Results: </strong>In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9x10<sup>-8</sup>), predominantly in the major histocompatibility complex, supporting an early-origins perspective on schizophrenia. Functional characterization confirmed strong genetic effects, 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. Differentially methylated regions were detected across PGSs (130-166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased explained variance for several cognitive and motor outcomes.</p><p><strong>Conclusions: </strong>Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm in the general population.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0000,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.\",\"authors\":\"Isabel K Schuurmans, Dinka Smajlagic, Vilte Baltramonaityte, Anni L K Malmberg, Alexander Neumann, Nicole Creasey, Janine F Felix, Henning Tiemeier, Jean-Baptiste Pingault, Darina Czamara, Katri Raïkkönen, Chistian Magnus Page, Robert Lyle, Alexandra Havdahl, Jari Lahti, Esther Walton, Mona Bekkhus, Charlotte A M Cecil\",\"doi\":\"10.1016/j.biopsych.2025.09.005\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. Yet, it is unclear whether: (i) genetic susceptibility to neurodevelopmental conditions associates with DNAm patterns already at birth; (ii) DNAm patterns are unique or shared across conditions, and (iii) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes.</p><p><strong>Methods: </strong>We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia (measured with polygenic scores [PGSs]) and cord blood DNAm in four European population-based cohorts (n<sub>pooled</sub>=5,802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Further, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years.</p><p><strong>Results: </strong>In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9x10<sup>-8</sup>), predominantly in the major histocompatibility complex, supporting an early-origins perspective on schizophrenia. Functional characterization confirmed strong genetic effects, 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. Differentially methylated regions were detected across PGSs (130-166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased explained variance for several cognitive and motor outcomes.</p><p><strong>Conclusions: </strong>Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm in the general population.</p>\",\"PeriodicalId\":8918,\"journal\":{\"name\":\"Biological Psychiatry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":9.0000,\"publicationDate\":\"2025-09-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biological Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.biopsych.2025.09.005\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.09.005","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.
Objective: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in fetal neurodevelopment. Epigenetic processes, such as DNA methylation (DNAm), are considered a key pathway of interest. Yet, it is unclear whether: (i) genetic susceptibility to neurodevelopmental conditions associates with DNAm patterns already at birth; (ii) DNAm patterns are unique or shared across conditions, and (iii) neonatal DNAm patterns can be leveraged to enhance genetic prediction of neurodevelopmental outcomes.
Methods: We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia (measured with polygenic scores [PGSs]) and cord blood DNAm in four European population-based cohorts (npooled=5,802; 50.2% female). We estimated DNAm pattern overlap between PGSs using heterogeneity statistics. Further, we built methylation profile scores for each PGS to test incremental variance explained over genetic data alone in 130 developmental outcomes from birth to 14 years.
Results: In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9x10-8), predominantly in the major histocompatibility complex, supporting an early-origins perspective on schizophrenia. Functional characterization confirmed strong genetic effects, 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. Differentially methylated regions were detected across PGSs (130-166 regions). Overall, DNAm signals were largely distinct between conditions. Incorporating neonatal DNAm data in genetic prediction models nominally increased explained variance for several cognitive and motor outcomes.
Conclusions: Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm in the general population.
期刊介绍：
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.
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