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  1. Article ; Online: Large-scale placenta DNA methylation integrated analysis reveals fetal sex-specific differentially methylated CpG sites and regions

    Shan V. Andrews / Irene J. Yang / Karolin Froehlich / Tomiko Oskotsky / Marina Sirota

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 15

    Abstract: Abstract Although male–female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) ... ...

    Abstract Abstract Although male–female differences in placental structure and function have been observed, little is understood about their molecular underpinnings. Here, we present a mega-analysis of 14 publicly available placenta DNA methylation (DNAm) microarray datasets to identify individual CpGs and regions associated with fetal sex. In the discovery dataset of placentas from full term pregnancies (N = 532 samples), 5212 CpGs met genome-wide significance (p < 1E−8) and were enriched in pathways such as keratinization (FDR p-value = 7.37E−14), chemokine activity (FDR p-value = 1.56E−2), and eosinophil migration (FDR p-value = 1.83E−2). Nine differentially methylated regions were identified (fwerArea < 0.1) including a region in the promoter of ZNF300 that showed consistent differential DNAm in samples from earlier timepoints in pregnancy and appeared to be driven predominately by effects in the trophoblast cell type. We describe the largest study of fetal sex differences in placenta DNAm performed to date, revealing genes and pathways characterizing sex-specific placenta function and health outcomes later in life.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pT73 Rab10

    Xiang Wang / Elvira Negrou / Michael T. Maloney / Vitaliy V. Bondar / Shan V. Andrews / Manuel Montalban / Ceyda Llapashtica / Romeo Maciuca / Hoang Nguyen / Hilda Solanoy / Annie Arguello / Laralynne Przybyla / Nathan J. Moerke / Sarah Huntwork-Rodriguez / Anastasia G. Henry

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 17

    Abstract: Abstract Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase ... ...

    Abstract Abstract Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying the disease-linked variant LRRK2 G2019S. Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Cross-tissue integration of genetic and epigenetic data offers insight into autism spectrum disorder

    Shan V. Andrews / Shannon E. Ellis / Kelly M. Bakulski / Brooke Sheppard / Lisa A. Croen / Irva Hertz-Picciotto / Craig J. Newschaffer / Andrew P. Feinberg / Dan E. Arking / Christine Ladd-Acosta / M. Daniele Fallin

    Nature Communications, Vol 8, Iss 1, Pp 1-

    2017  Volume 10

    Abstract: There have been a number of recent epigenetic studies on autism spectrum disorder. Here, the authors integrate genetic and epigenetic data from cord and peripheral blood and also from brain tissues to show the potential of blood-based epigenetic data to ...

    Abstract “There have been a number of recent epigenetic studies on autism spectrum disorder. Here, the authors integrate genetic and epigenetic data from cord and peripheral blood and also from brain tissues to show the potential of blood-based epigenetic data to provide insights into psychiatric disorders.”
    Keywords Science ; Q
    Language English
    Publishing date 2017-10-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  4. Article ; Online: Elevated polygenic burden for autism is associated with differential DNA methylation at birth

    Eilis Hannon / Diana Schendel / Christine Ladd-Acosta / Jakob Grove / iPSYCH-Broad ASD Group / Christine Søholm Hansen / Shan V. Andrews / David Michael Hougaard / Michaeline Bresnahan / Ole Mors / Mads Vilhelm Hollegaard / Marie Bækvad-Hansen / Mady Hornig / Preben Bo Mortensen / Anders D. Børglum / Thomas Werge / Marianne Giørtz Pedersen / Merete Nordentoft / Joseph Buxbaum /
    M. Daniele Fallin / Jonas Bybjerg-Grauholm / Abraham Reichenberg / Jonathan Mill

    Genome Medicine, Vol 10, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Abstract Background Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and ... ...

    Abstract Abstract Background Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder characterized by deficits in social communication and restricted, repetitive behaviors, interests, or activities. The etiology of ASD involves both inherited and environmental risk factors, with epigenetic processes hypothesized as one mechanism by which both genetic and non-genetic variation influence gene regulation and pathogenesis. The aim of this study was to identify DNA methylation biomarkers of ASD detectable at birth. Methods We quantified neonatal methylomic variation in 1263 infants—of whom ~ 50% went on to subsequently develop ASD—using DNA isolated from archived blood spots taken shortly after birth. We used matched genotype data from the same individuals to examine the molecular consequences of ASD-associated genetic risk variants, identifying methylomic variation associated with elevated polygenic burden for ASD. In addition, we performed DNA methylation quantitative trait loci (mQTL) mapping to prioritize target genes from ASD GWAS findings. Results We identified robust epigenetic signatures of gestational age and prenatal tobacco exposure, confirming the utility of DNA methylation data generated from neonatal blood spots. Although we did not identify specific loci showing robust differences in neonatal DNA methylation associated with later ASD, there was a significant association between increased polygenic burden for autism and methylomic variation at specific loci. Each unit of elevated ASD polygenic risk score was associated with a mean increase in DNA methylation of − 0.14% at two CpG sites located proximal to a robust GWAS signal for ASD on chromosome 8. Conclusions This study is the largest analysis of DNA methylation in ASD undertaken and the first to integrate genetic and epigenetic variation at birth. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with disease, and of using mQTL to refine the functional and regulatory variation associated with ASD risk variants.
    Keywords Autism ; DNA methylation ; Genetics ; Neonatal ; Genome-wide association study (GWAS) ; Epigenome-wide association study (EWAS) ; Medicine ; R ; QH426-470
    Subject code 610
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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