An epigenome-wide association study in the case-control study to explore early development identifies differential DNA methylation near ZFP57 as associated with autistic traits / Ellen M. HOWERTON in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : An epigenome-wide association study in the case-control study to explore early development identifies differential DNA methylation near ZFP57 as associated with autistic traits Type de document : texte imprimé Auteurs : Ellen M. HOWERTON, Auteur ; Valerie MORRILL, Auteur ; Rose SCHROTT, Auteur ; Jason DANIELS, Auteur ; Ashley Y. SONG, Auteur ; Kelly BENKE, Auteur ; Heather VOLK, Auteur ; Homayoon FARZADEGAN, Auteur ; Aimee ANIDO ALEXANDER, Auteur ; Amanda L. TAPIA, Auteur ; Gabriel S. DICHTER, Auteur ; Lisa A. CROEN, Auteur ; Lisa WIGGINS, Auteur ; Genevieve WOJCIK, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur Langues : Anglais (eng) Mots-clés : Humans  DNA Methylation/genetics  Male  Female  Case-Control Studies  Genome-Wide Association Study  Autism Spectrum Disorder/genetics  Child, Preschool  DNA-Binding Proteins/genetics  Transcription Factors/genetics  Epigenome  Quantitative Trait Loci  Repressor Proteins  Autism  DNA methylation  Quantitative trait  Social Responsiveness Scale  by the institutional review boards (IRBs) at each SEED site. SEED 1 recruitment  was approved by the IRB of each recruitment site: IRB-C, CDC Human Research  Protection Office  Kaiser Foundation Research Institute (KFRI) Kaiser Permanente  Northern California IRB, Colorado Multiple IRB, Emory University IRB, Georgia  Department of Public Health IRB, Maryland Department of Health and Mental Hygiene  IRB, Johns Hopkins Bloomberg School of Public Health IRB, University of North  Carolina IRB and Office of Human Research Ethics, IRB of The Children’s Hospital  of Philadelphia, and IRB of the University of Pennsylvania. All enrolled families  provided written consent for participation. Consent for publication: Not  applicable. Competing interests: CLA reports receiving consulting fees from the  University of Iowa for providing expertise on epigenetics outside of this work.  All other authors declare that they have no conflict of interest. The findings  and conclusions in this report are those of the authors and do not necessarily  represent the official position of the Centers for Disease Control and  Prevention. Index. décimale : PER Périodiques Résumé : BACKGROUND: Quantitative measures of autism spectrum disorder (ASD)-related traits can provide insight into trait presentation across the population. Previous studies have identified epigenomic variation associated with ASD diagnosis, but few have evaluated quantitative traits. We sought to identify DNA methylation patterns in child blood associated with Social Responsiveness Scale score, Second Edition (SRS). METHODS: We conducted an epigenome-wide association study of SRS in child blood at approximately age 5 in the Study to Explore Early Development, a case-control study of ASD in the United States. We measured DNA methylation using the Illumina 450K array with 857 samples in our analysis after quality control. We performed regression of the M-value to identify single sites or differentially methylated regions (DMRs) associated with SRS scores, adjusting for sources of biological and technical variation. We examined methylation quantitative trait loci and conducted gene-ontology-term pathway analyses for regions of interest. RESULTS: We identified a region about 3.5 kb upstream of ZFP57 on chromosome 6 as differentially methylated (family-wise error rate [fwer] < 0.1) by continuous SRS T-score in the full sample (N = 857; fwer = 0.074) and among ASD cases only (N = 390; fwer = 0.021). ZFP57 encodes a transcription factor involved in imprinting regulation and maintenance, and this DMR has been previously associated with ASD in brain and buccal samples. CONCLUSIONS: Blood DNA methylation near ZFP57 was associated (fwer < 0.1) with SRS in the full population sample and appears to be largely driven by trait heterogeneity within the autism case group. Our results indicate DNA methylation associations with ASD quantitative traits are observable in a population and provide insights into specific biologic changes related to autism trait heterogeneity. En ligne : https://dx.doi.org/10.1186/s11689-025-09637-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] An epigenome-wide association study in the case-control study to explore early development identifies differential DNA methylation near ZFP57 as associated with autistic traits [texte imprimé] / Ellen M. HOWERTON, Auteur ; Valerie MORRILL, Auteur ; Rose SCHROTT, Auteur ; Jason DANIELS, Auteur ; Ashley Y. SONG, Auteur ; Kelly BENKE, Auteur ; Heather VOLK, Auteur ; Homayoon FARZADEGAN, Auteur ; Aimee ANIDO ALEXANDER, Auteur ; Amanda L. TAPIA, Auteur ; Gabriel S. DICHTER, Auteur ; Lisa A. CROEN, Auteur ; Lisa WIGGINS, Auteur ; Genevieve WOJCIK, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Humans  DNA Methylation/genetics  Male  Female  Case-Control Studies  Genome-Wide Association Study  Autism Spectrum Disorder/genetics  Child, Preschool  DNA-Binding Proteins/genetics  Transcription Factors/genetics  Epigenome  Quantitative Trait Loci  Repressor Proteins  Autism  DNA methylation  Quantitative trait  Social Responsiveness Scale  by the institutional review boards (IRBs) at each SEED site. SEED 1 recruitment  was approved by the IRB of each recruitment site: IRB-C, CDC Human Research  Protection Office  Kaiser Foundation Research Institute (KFRI) Kaiser Permanente  Northern California IRB, Colorado Multiple IRB, Emory University IRB, Georgia  Department of Public Health IRB, Maryland Department of Health and Mental Hygiene  IRB, Johns Hopkins Bloomberg School of Public Health IRB, University of North  Carolina IRB and Office of Human Research Ethics, IRB of The Children’s Hospital  of Philadelphia, and IRB of the University of Pennsylvania. All enrolled families  provided written consent for participation. Consent for publication: Not  applicable. Competing interests: CLA reports receiving consulting fees from the  University of Iowa for providing expertise on epigenetics outside of this work.  All other authors declare that they have no conflict of interest. The findings  and conclusions in this report are those of the authors and do not necessarily  represent the official position of the Centers for Disease Control and  Prevention. Index. décimale : PER Périodiques Résumé : BACKGROUND: Quantitative measures of autism spectrum disorder (ASD)-related traits can provide insight into trait presentation across the population. Previous studies have identified epigenomic variation associated with ASD diagnosis, but few have evaluated quantitative traits. We sought to identify DNA methylation patterns in child blood associated with Social Responsiveness Scale score, Second Edition (SRS). METHODS: We conducted an epigenome-wide association study of SRS in child blood at approximately age 5 in the Study to Explore Early Development, a case-control study of ASD in the United States. We measured DNA methylation using the Illumina 450K array with 857 samples in our analysis after quality control. We performed regression of the M-value to identify single sites or differentially methylated regions (DMRs) associated with SRS scores, adjusting for sources of biological and technical variation. We examined methylation quantitative trait loci and conducted gene-ontology-term pathway analyses for regions of interest. RESULTS: We identified a region about 3.5 kb upstream of ZFP57 on chromosome 6 as differentially methylated (family-wise error rate [fwer] < 0.1) by continuous SRS T-score in the full sample (N = 857; fwer = 0.074) and among ASD cases only (N = 390; fwer = 0.021). ZFP57 encodes a transcription factor involved in imprinting regulation and maintenance, and this DMR has been previously associated with ASD in brain and buccal samples. CONCLUSIONS: Blood DNA methylation near ZFP57 was associated (fwer < 0.1) with SRS in the full population sample and appears to be largely driven by trait heterogeneity within the autism case group. Our results indicate DNA methylation associations with ASD quantitative traits are observable in a population and provide insights into specific biologic changes related to autism trait heterogeneity. En ligne : https://dx.doi.org/10.1186/s11689-025-09637-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder / Michael YAO in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder Type de document : texte imprimé Auteurs : Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Commonly used genomic arrays may lose information due to imperfect coverage of discovered variants for autism spectrum disorder [texte imprimé] / Michael YAO, Auteur ; Jason DANIELS, Auteur ; Luke GROSVENOR, Auteur ; Valerie MORRILL, Auteur ; Jason I. FEINBERG, Auteur ; Kelly M. BAKULSKI, Auteur ; Joseph PIVEN, Auteur ; Heather C. HAZLETT, Auteur ; Mark D. SHEN, Auteur ; Craig NEWSCHAFFER, Auteur ; Kristen LYALL, Auteur ; Rebecca J. SCHMIDT, Auteur ; Irva HERTZ-PICCIOTTO, Auteur ; Lisa A. CROEN, Auteur ; M. Daniele FALLIN, Auteur ; Christine LADD-ACOSTA, Auteur ; Heather VOLK, Auteur ; Kelly BENKE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Autism Spectrum Disorder/genetics  Genome-Wide Association Study  Multifactorial Inheritance  Genetic Predisposition to Disease  Male  Female  Genotype  Polymorphism, Single Nucleotide  Autism spectrum disorder (ASD)  Information Loss  Polygenic scores (PGS) Index. décimale : PER Périodiques Résumé : BACKGROUND: Common genetic variation has been shown to account for a large proportion of ASD heritability. Polygenic scores generated for autism spectrum disorder (ASD-PGS) using the most recent discovery data, however, explain less variance than expected, despite reporting significant associations with ASD and other ASD-related traits. Here, we investigate the extent to which information loss on the target study genome-wide microarray weakens the predictive power of the ASD-PGS. METHODS: We studied genotype data from three cohorts of individuals with high familial liability for ASD: The Early Autism Risk Longitudinal Investigation (EARLI), Markers of Autism Risk in Babies-Learning Early Signs (MARBLES), and the Infant Brain Imaging Study (IBIS), and one population-based sample, Study to Explore Early Development Phase I (SEED I). Individuals were genotyped on different microarrays ranging from 1 to 5 million sites. Coverage of the top 88 genome-wide suggestive variants implicated in the discovery was evaluated in all four studies before quality control (QC), after QC, and after imputation. We then created a novel method to assess coverage on the resulting ASD-PGS by correlating a PGS informed by a comprehensive list of variants to a PGS informed with only the available variants. RESULTS: Prior to imputations, None of the four cohorts directly or indirectly covered all 88 variants among the measured genotype data. After imputation, the two cohorts genotyped on 5-million arrays reached full coverage. Analysis of our novel metric showed generally high genome-wide coverage across all four studies, but a greater number of SNPs informing the ASD-PGS did not result in improved coverage according to our metric. LIMITATIONS: The studies we analyzed contained modest sample sizes. Our analyses included microarrays with more than 1-million sites, so smaller arrays such as Global Diversity and the PsychArray were not included. Our PGS metric for ASD is only generalizable to samples of European ancestries, though the coverage metric can be computed for traits that have sufficiently large-sized discovery findings in other ancestries. CONCLUSIONS: We show that commonly used genotyping microarrays have incomplete coverage for common ASD variants, and imputation cannot always recover lost information. Our novel metric provides an intuitive approach to reporting information loss in PGS and an alternative to reporting the total number of SNPs included in the PGS. While applied only to ASD here, this metric can easily be used with other traits. En ligne : https://dx.doi.org/10.1186/s11689-024-09571-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

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