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218 results on '"Chiocchetti, Andreas G."'

1. Effectiveness of a positive psychology and mindfulness-based app on mental health for parents of children with a neurodevelopmental disorder: study protocol of a pragmatic international randomized controlled trial

Author

Tönis, Kim J. M., Drossaert, Constance H. C., ten Klooster, Peter M., Schaer, Marie, Bourgeron, Thomas, Buitelaar, Jan K., Sadaka, Yair, Freitag, Christine M., Lapidus, Keren Mayer, Chiocchetti, Andreas G., Staal, Wouter G., and Bohlmeijer, Ernst T.

Published
2024
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2. Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype

Author

Breen, Michael S, Garg, Paras, Tang, Lara, Mendonca, Danielle, Levy, Tess, Barbosa, Mafalda, Arnett, Anne B, Kurtz-Nelson, Evangeline, Agolini, Emanuele, Battaglia, Agatino, Chiocchetti, Andreas G, Freitag, Christine M, Garcia-Alcon, Alicia, Grammatico, Paola, Hertz-Picciotto, Irva, Ludena-Rodriguez, Yunin, Moreno, Carmen, Novelli, Antonio, Parellada, Mara, Pascolini, Giulia, Tassone, Flora, Grice, Dorothy E, Di Marino, Daniele, Bernier, Raphael A, Kolevzon, Alexander, Sharp, Andrew J, Buxbaum, Joseph D, Siper, Paige M, and De Rubeis, Silvia

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Brain Disorders, Basic Behavioral and Social Science, Intellectual and Developmental Disabilities (IDD), Mental Health, Behavioral and Social Science, Autism, Neurosciences, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Autism Spectrum Disorder, Child, DNA Methylation, Developmental Disabilities, Epigenesis, Genetic, Female, Homeodomain Proteins, Humans, Intellectual Disability, Male, Mutation, Nerve Tissue Proteins, Neurodevelopmental Disorders, Phenotype, Transcriptome, ADNP, DNA methylation, Helsmoortel-Van der Aa syndrome, autism spectrum disorder, biomarkers, epigenetic signature, episignature, genotype-phenotype correlations, intellectual disability, neurodevelopmental disorders, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.

Published
2020

3. Publisher Correction: Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D’Gama, Alissa M, Kim, Sonia N, Hill, Robert Sean, Goldberg, Arthur P, Poultney, Christopher, Minshew, Nancy J, Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J, Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M, Weiss, Lauren A, Fromer, Menachem, Chiocchetti, Andreas G, Freitag, Christine M, Church, George M, Scherer, Stephen W, Buxbaum, Joseph D, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

4. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Satterstrom, F Kyle, Kosmicki, Jack A, Wang, Jiebiao, Breen, Michael S, De Rubeis, Silvia, An, Joon-Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S, Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E, Dias, Caroline, Consortium, Autism Sequencing, Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus CY, Chiocchetti, Andreas G, Chung, Brian HY, Coon, Hilary, Cuccaro, Michael L, Curró, Aurora, Bernardina, Bernardo Dalla, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Freitag, Christine M, Fromer, Menachem, Gargus, J Jay, Geschwind, Daniel, Giorgio, Elisa, González-Peñas, Javier, Guter, Stephen, Halpern, Danielle, Hansen-Kiss, Emily, He, Xin, Herman, Gail E, Hertz-Picciotto, Irva, Hougaard, David M, Hultman, Christina M, Ionita-Laza, Iuliana, Jacob, Suma, Jamison, Jesslyn, Jugessur, Astanand, Kaartinen, Miia, Knudsen, Gun Peggy, Kolevzon, Alexander, Kushima, Itaru, Lee, So Lun, Lehtimäki, Terho, Lim, Elaine T, Lintas, Carla, Lipkin, W Ian, Lopergolo, Diego, Lopes, Fátima, Ludena, Yunin, Maciel, Patricia, Magnus, Per, Mahjani, Behrang, Maltman, Nell, Manoach, Dara S, Meiri, Gal, Menashe, Idan, Miller, Judith, Minshew, Nancy, Montenegro, Eduarda MS, Moreira, Danielle, Morrow, Eric M, Mors, Ole, Mortensen, Preben Bo, Mosconi, Matthew, Muglia, Pierandrea, Neale, Benjamin M, Nordentoft, Merete, Ozaki, Norio, Palotie, Aarno, Parellada, Mara, Passos-Bueno, Maria Rita, Pericak-Vance, Margaret, Persico, Antonio M, and Pessah, Isaac

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Mental Health, Pediatric, Human Genome, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Exome Sequencing, Autism Sequencing Consortium, iPSYCH-Broad Consortium, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, excitatory-inhibitory balance, exome sequencing, genetics, inhibitory neurons, liability, neurodevelopment, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Published
2020

7. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author

Guissart, Claire, Latypova, Xenia, Rollier, Paul, Khan, Tahir N, Stamberger, Hannah, McWalter, Kirsty, Cho, Megan T, Kjaergaard, Susanne, Weckhuysen, Sarah, Lesca, Gaetan, Besnard, Thomas, Õunap, Katrin, Schema, Lynn, Chiocchetti, Andreas G, McDonald, Marie, de Bellescize, Julitta, Vincent, Marie, Van Esch, Hilde, Sattler, Shannon, Forghani, Irman, Thiffault, Isabelle, Freitag, Christine M, Barbouth, Deborah Sara, Cadieux-Dion, Maxime, Willaert, Rebecca, Sacoto, Maria J Guillen, Safina, Nicole P, Dubourg, Christèle, Grote, Lauren, Carré, Wilfrid, Saunders, Carol, Pajusalu, Sander, Farrow, Emily, Boland, Anne, Karlowicz, Danielle Hays, Deleuze, Jean-François, Wojcik, Monica H, Pressman, Rena, Isidor, Bertrand, Vogels, Annick, Van Paesschen, Wim, Al-Gazali, Lihadh, Shamsi, Aisha Mohamed Al, Claustres, Mireille, Pujol, Aurora, Sanders, Stephan J, Rivier, François, Leboucq, Nicolas, Cogné, Benjamin, Sasorith, Souphatta, Sanlaville, Damien, Retterer, Kyle, Odent, Sylvie, Katsanis, Nicholas, Bézieau, Stéphane, Koenig, Michel, Davis, Erica E, Pasquier, Laurent, and Küry, Sébastien

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Neurosciences, Pediatric, Rare Diseases, Brain Disorders, Autism, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, DNA Copy Number Variations, Disease Models, Animal, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish, RORA, autistic features, cerebellar ataxia, dual molecular effects, epilepsy, intellectual disability, neurodevelopmental disorder, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Published
2018

8. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D'Gama, Alissa M, Kim, Sonia N, Hill, Robert Sean, Goldberg, Arthur P, Poultney, Christopher, Minshew, Nancy J, Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J, Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M, Weiss, Lauren A, Fromer, Menachem, Chiocchetti, Andreas G, Freitag, Christine M, Church, George M, Scherer, Stephen W, Buxbaum, Joseph D, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Autism, Genetics, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Published
2017

9. Dual Role of microRNA-146a in Experimental Inflammation in Human Pulmonary Epithelial and Immune Cells and Expression in Inflammatory Lung Diseases.

Author

Gronau, Lucia, Duecker, Ruth P., Jerkic, Silvija-Pera, Eickmeier, Olaf, Trischler, Jordis, Chiocchetti, Andreas G., Blumchen, Katharina, Zielen, Stefan, and Schubert, Ralf

Subjects
LUNG diseases, EPITHELIAL cells, BRONCHIOLITIS obliterans, INFLAMMATION, CYSTIC fibrosis
Abstract

microRNA (miR)-146a emerges as a promising post-transcriptional regulator in various inflammatory diseases with different roles for the two isoforms miR-146a-5p and miR-146a-3p. The present study aimed to examine the dual role of miR-146a-5p and miR-146a 3p in the modulation of inflammation in human pulmonary epithelial and immune cells in vitro as well as their expression in patients with inflammatory lung diseases. Experimental inflammation in human A549, HL60, and THP1 via the NF-kB pathway resulted in the major upregulation of miR-146a-5p and miR-146a-3p expression, which was partly cell-specific. Modulation by transfection with miRNA mimics and inhibitors demonstrated an anti-inflammatory effect of miR-146a-5p and a pro-inflammatory effect of miR-146a-3p, respectively. A mutual interference between miR-146a-5p and miR-146a-3p was observed, with miR-146a-5p exerting a predominant influence. In vivo NGS analyses revealed an upregulation of miR-146a-3p in the blood of patients with cystic fibrosis and bronchiolitis obliterans, while miR-146a-5p levels were downregulated or unchanged compared to controls. The reverse pattern was observed in patients with SARS-CoV-2 infection. In conclusion, miR-146a-5p and miR-146a-3p are two distinct but interconnected miRNA isoforms with opposing functions in inflammation regulation. Understanding their interaction provides important insights into the progression and persistence of inflammatory lung diseases and might provide potential therapeutic options. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Interferon regulatory factor 4 plays a pivotal role in the development of aGVHD-associated colitis

Author

Frueh, Jochen T., primary, Campe, Julia, additional, Sunaga-Franze, Daniele Yumi, additional, Verheyden, Nikita A., additional, Ghimire, Sakhila, additional, Meedt, Elisabeth, additional, Haslinger, Denise, additional, Harenkamp, Sabine, additional, Staudenraus, Daniel, additional, Sauer, Sascha, additional, Kreft, Andreas, additional, Schubert, Ralf, additional, Lohoff, Michael, additional, Krueger, Andreas, additional, Bonig, Halvard, additional, Chiocchetti, Andreas G., additional, Zeiser, Robert, additional, Holler, Ernst, additional, and Ullrich, Evelyn, additional

Published
2023
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12. Correction: SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study

Author

Farrow, Elizabeth, Chiocchetti, Andreas G., Rogers, Jack C., Pauli, Ruth, Raschle, Nora M., Gonzalez-Madruga, Karen, Smaragdi, Areti, Martinelli, Anne, Kohls, Gregor, Stadler, Christina, Konrad, Kerstin, Fairchild, Graeme, Freitag, Christine M., Chechlacz, Magdalena, and De Brito, Stephane A.

Published
2021
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15. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Author

Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao, Ziman, Robert, Wang, Zhuozhi, Vorstman, Jacob AS, Thompson, Ann, Regan, Regina, Pilorge, Marion, Pellecchia, Giovanna, Pagnamenta, Alistair T, Oliveira, Bárbara, Marshall, Christian R, Magalhaes, Tiago R, Lowe, Jennifer K, Howe, Jennifer L, Griswold, Anthony J, Gilbert, John, Duketis, Eftichia, Dombroski, Beth A, De Jonge, Maretha V, Cuccaro, Michael, Crawford, Emily L, Correia, Catarina T, Conroy, Judith, Conceição, Inês C, Chiocchetti, Andreas G, Casey, Jillian P, Cai, Guiqing, Cabrol, Christelle, Bolshakova, Nadia, Bacchelli, Elena, Anney, Richard, Gallinger, Steven, Cotterchio, Michelle, Casey, Graham, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wing, Kirsty, Wallace, Simon, van Engeland, Herman, Tryfon, Ana, Thomson, Susanne, Soorya, Latha, Rogé, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy, McInnes, L Alison, McGrew, Susan G, Lord, Catherine, Leboyer, Marion, Le Couteur, Ann S, Kolevzon, Alexander, González, Patricia Jiménez, Jacob, Suma, Holt, Richard, Guter, Stephen, Green, Jonathan, Green, Andrew, Gillberg, Christopher, Fernandez, Bridget A, Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Chaste, Pauline, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F, Bölte, Sven, Bernier, Raphael, Baird, Gillian, Bailey, Anthony J, Anagnostou, Evdokia, Almeida, Joana, Wijsman, Ellen M, Vieland, Veronica J, Vicente, Astrid M, Schellenberg, Gerard D, Pericak-Vance, Margaret, Paterson, Andrew D, Parr, Jeremy R, Oliveira, Guiomar, Nurnberger, John I, Monaco, Anthony P, Maestrini, Elena, Klauck, Sabine M, Hakonarson, Hakon, Haines, Jonathan L, Geschwind, Daniel H, Freitag, Christine M, Folstein, Susan E, and Ennis, Sean

Subjects
Genetics, Brain Disorders, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Neurosciences, Autism, 2.1 Biological and endogenous factors, Aetiology, Child, Child Development Disorders, Pervasive, DNA Copy Number Variations, Female, Gene Regulatory Networks, Humans, Male, Metabolic Networks and Pathways, Multigene Family, Pedigree, Sequence Deletion, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Published
2014

16. Recessive gene disruptions in autism spectrum disorder

Author

Doan, Ryan N., Lim, Elaine T., De Rubeis, Silvia, Betancur, Catalina, Cutler, David J., Chiocchetti, Andreas G., Overman, Lynne M., Soucy, Aubrie, Goetze, Susanne, Autism Sequencing Consortium, Freitag, Christine M., Daly, Mark J., Walsh, Christopher A., Buxbaum, Joseph D., and Yu, Timothy W.

Published
2019
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18. The role of rare compound heterozygous events in autism spectrum disorder

Author

Lin, Bochao Danae, Colas, Fabrice, Nijman, Isaac J., Medic, Jelena, Brands, William, Parr, Jeremy R., van Eijk, Kristel R., Klauck, Sabine M., Chiocchetti, Andreas G., Freitag, Christine M., Maestrini, Elena, Bacchelli, Elena, Coon, Hilary, Vicente, Astrid, Oliveira, Guiomar, Pagnamenta, Alistair T., Gallagher, Louise, Ennis, Sean, Anney, Richard, Bourgeron, Thomas, Luykx, Jurjen J., and Vorstman, Jacob

Published
2020
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20. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Author

Rots, Dmitrijs, primary, Jakub, Taryn E., additional, Keung, Crystal, additional, Jackson, Adam, additional, Banka, Siddharth, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Jaarsveld, Richard H., additional, Hopman, Saskia M.J., additional, van Binsbergen, Ellen, additional, Valenzuela, Irene, additional, Hempel, Maja, additional, Bierhals, Tatjana, additional, Kortüm, Fanny, additional, Lecoquierre, Francois, additional, Goldenberg, Alice, additional, Hertz, Jens Michael, additional, Andersen, Charlotte Brasch, additional, Kibæk, Maria, additional, Prijoles, Eloise J., additional, Stevenson, Roger E., additional, Everman, David B., additional, Patterson, Wesley G., additional, Meng, Linyan, additional, Gijavanekar, Charul, additional, De Dios, Karl, additional, Lakhani, Shenela, additional, Levy, Tess, additional, Wagner, Matias, additional, Wieczorek, Dagmar, additional, Benke, Paul J., additional, Lopez Garcia, María Soledad, additional, Perrier, Renee, additional, Sousa, Sergio B., additional, Almeida, Pedro M., additional, Simões, Maria José, additional, Isidor, Bertrand, additional, Deb, Wallid, additional, Schmanski, Andrew A., additional, Abdul-Rahman, Omar, additional, Philippe, Christophe, additional, Bruel, Ange-Line, additional, Faivre, Laurence, additional, Vitobello, Antonio, additional, Thauvin, Christel, additional, Smits, Jeroen J., additional, Garavelli, Livia, additional, Caraffi, Stefano G., additional, Peluso, Francesca, additional, Davis-Keppen, Laura, additional, Platt, Dylan, additional, Royer, Erin, additional, Leeuwen, Lisette, additional, Sinnema, Margje, additional, Stegmann, Alexander P.A., additional, Stumpel, Constance T.R.M., additional, Tiller, George E., additional, Bosch, Daniëlle G.M., additional, Potgieter, Stephanus T., additional, Joss, Shelagh, additional, Splitt, Miranda, additional, Holden, Simon, additional, Prapa, Matina, additional, Foulds, Nicola, additional, Douzgou, Sofia, additional, Puura, Kaija, additional, Waltes, Regina, additional, Chiocchetti, Andreas G., additional, Freitag, Christine M., additional, Satterstrom, F. Kyle, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph, additional, Gelb, Bruce D., additional, Branko, Aleksic, additional, Kushima, Itaru, additional, Howe, Jennifer, additional, Scherer, Stephen W., additional, Arado, Alessia, additional, Baldo, Chiara, additional, Patat, Olivier, additional, Bénédicte, Demeer, additional, Lopergolo, Diego, additional, Santorelli, Filippo M., additional, Haack, Tobias B., additional, Dufke, Andreas, additional, Bertrand, Miriam, additional, Falb, Ruth J., additional, Rieß, Angelika, additional, Krieg, Peter, additional, Spranger, Stephanie, additional, Bedeschi, Maria Francesca, additional, Iascone, Maria, additional, Josephi-Taylor, Sarah, additional, Roscioli, Tony, additional, Buckley, Michael F., additional, Liebelt, Jan, additional, Dagli, Aditi I., additional, Aten, Emmelien, additional, Hurst, Anna C.E., additional, Hicks, Alesha, additional, Suri, Mohnish, additional, Aliu, Ermal, additional, Naik, Sunil, additional, Sidlow, Richard, additional, Coursimault, Juliette, additional, Nicolas, Gaël, additional, Küpper, Hanna, additional, Petit, Florence, additional, Ibrahim, Veyan, additional, Top, Deniz, additional, Di Cara, Francesca, additional, Louie, Raymond J., additional, Stolerman, Elliot, additional, Brunner, Han G., additional, Vissers, Lisenka E.L.M., additional, Kramer, Jamie M., additional, and Kleefstra, Tjitske, additional

Published
2023
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26. ADHD‐associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

Author

Radtke, Franziska, primary, Palladino, Viola Stella, additional, McNeill, Rhiannon V., additional, Chiocchetti, Andreas G., additional, Haslinger, Denise, additional, Leyh, Matthias, additional, Gersic, Danijel, additional, Frank, Markus, additional, Grünewald, Lena, additional, Klebe, Stephan, additional, Brüstle, Oliver, additional, Günther, Katharina, additional, Edenhofer, Frank, additional, Kranz, Thorsten M., additional, Reif, Andreas, additional, and Kittel‐Schneider, Sarah, additional

Published
2022
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29. The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors

Author

Chiocchetti, Andreas G., Yousaf, Afsheen, Kohls, Gregor, Vetro, Agnes, Hervas, Amaia, Fernández-Rivas, Aranzazu, Freitag, Christine M., Waltes, Regina, Bernhard, Anka, Martinelli, Anne, Ackermann, Katharina, Haslinger, Denise, Rotter, Björn, Krezdorn, Nico, and Konrad, Kerstin

Subjects
Environmental Impacts, Conduct Disorder, Cell biology, Computer and Information Sciences, Adolescent, Epidemiology, Science, Gene Identification and Analysis, Social Sciences, Genetic Networks, Biochemistry, Methylation, Hippocampus, Cell Line, Epigenesis, Genetic, Epigenome, Risk Factors, Genetics, Medicine and Health Sciences, Psychology, Humans, Gene Regulatory Networks, ddc:610, Behavior, DNA methylation, Biology and life sciences, Ecology and Environmental Sciences, Chemical Reactions, DNA, Chromatin, Nucleic acids, Aggression, Chemistry, Medical Risk Factors, Physical Sciences, Medicine, Epigenetics, Female, Gene expression, DNA modification, Chromatin modification, Network Analysis, Research Article, Chromosome biology, Genome-Wide Association Study
Abstract

PLOS ONE 17(1), 1-7 (2022). doi:10.1371/journal.pone.0261691, Published by PLOS, San Francisco, California, US

Published
2022

30. The MiR-320 Family Is Strongly Downregulated in Patients with COVID-19 Induced Severe Respiratory Failure

Author

Dücker, Ruth Pia, Adam, Elisabeth, Wirtz, Sarah, Gronau, Lucia, Khodamoradi, Yascha, Eberhardt, Fabian J., Donath, Helena, Gutmann, Desiree, Vehreschild, Maria J. G. T., Zacharowski, Kai, Kreyenberg, Hermann, Chiocchetti, Andreas G., Zielen, Stefan, and Schubert, Ralf

Subjects
Male, lung disease, QH301-705.5, Down-Regulation, Severity of Illness Index, Article, Humans, ddc:610, Biology (General), QD1-999, Blood Coagulation, Aged, miRNA, Aged, 80 and over, Inflammation, SARS-CoV-2, respiratory failure, COVID-19, Middle Aged, Chemistry, MicroRNAs, D-dimer, Disease Progression, Female, Respiratory Insufficiency, CRP
Abstract

A high incidence of thromboembolic events associated with high mortality has been reported in severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections with respiratory failure. The present study characterized post-transcriptional gene regulation by global microRNA (miRNA) expression in relation to activated coagulation and inflammation in 21 critically ill SARS-CoV-2 patients. The cohort consisted of patients with moderate respiratory failure (n = 11) and severe respiratory failure (n = 10) at an acute stage (day 0–3) and in the later course of the disease (&gt, 7 days). All patients needed supplemental oxygen and severe patients were defined by the requirement of positive pressure ventilation (intubation). Levels of D-dimers, activated partial thromboplastin time (aPTT), C-reactive protein (CRP), and interleukin (IL)-6 were significantly higher in patients with severe compared with moderate respiratory failure. Concurrently, next generation sequencing (NGS) analysis demonstrated increased dysregulation of miRNA expression with progression of disease severity connected to extreme downregulation of miR-320a, miR-320b and miR-320c. Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis revealed involvement in the Hippo signaling pathway, the transforming growth factor (TGF)-β signaling pathway and in the regulation of adherens junctions. The expression of all miR-320 family members was significantly correlated with CRP, IL-6, and D-dimer levels. In conclusion, our analysis underlines the importance of thromboembolic processes in patients with respiratory failure and emphasizes miRNA-320s as potential biomarkers for severe progressive SARS-CoV-2 infection.

Published
2021

33. Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders

Author

Waltes, Regina, Duketis, Eftichia, Knapp, Michael, Anney, Richard J. L., Huguet, Guillaume, Schlitt, Sabine, Jarczok, Tomasz A., Sachse, Michael, Kämpfer, Laura M., Kleinböck, Tina, Poustka, Fritz, Bölte, Sven, Schmötzer, Gabriele, Voran, Anette, Huy, Ellen, Meyer, Jobst, Bourgeron, Thomas, Klauck, Sabine M., Freitag, Christine M., and Chiocchetti, Andreas G.

Published
2014
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35. The MiR-320 Family Is Strongly Downregulated in Patients with COVID-19 Induced Severe Respiratory Failure

Author

Duecker, Ruth P., primary, Adam, Elisabeth H., additional, Wirtz, Sarah, additional, Gronau, Lucia, additional, Khodamoradi, Yascha, additional, Eberhardt, Fabian J., additional, Donath, Helena, additional, Gutmann, Desiree, additional, Vehreschild, Maria J. G. T., additional, Zacharowski, Kai, additional, Kreyenberg, Hermann, additional, Chiocchetti, Andreas G., additional, Zielen, Stefan, additional, and Schubert, Ralf, additional

Published
2021
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36. Synaptic, transcriptional and chromatin genes disrupted in autism

Author

De Rubeis, Silvia, He, Xin, Goldberg, Arthur P., Poultney, Christopher S., Samocha, Kaitlin, Cicek, Ercument A., Kou, Yan, Liu, Li, Fromer, Menachem, Walker, Susan, Singh, Tarjinder, Klei, Lambertus, Kosmicki, Jack, Fu, Shih-Chen, Aleksic, Branko, Biscaldi, Monica, Bolton, Patrick F., Brownfeld, Jessica M., Cai, Jinlu, Campbell, Nicholas G., Carracedo, Angel, Chahrour, Maria H., Chiocchetti, Andreas G., Coon, Hilary, Crawford, Emily L., Crooks, Lucy, Curran, Sarah R., Dawson, Geraldine, Duketis, Eftichia, Fernandez, Bridget A., Gallagher, Louise, Geller, Evan, Guter, Stephen J., Hill, Sean R., Ionita-Laza, Iuliana, Gonzalez, Patricia Jimenez, Kilpinen, Helena, Klauck, Sabine M., Kolevzon, Alexander, Lee, Irene, Lei, Jing, Lehtimäki, Terho, Lin, Chiao-Feng, Maʼayan, Avi, Marshall, Christian R., McInnes, Alison L., Neale, Benjamin, Owen, Michael J., Ozaki, Norio, Parellada, Mara, Parr, Jeremy R., Purcell, Shaun, Puura, Kaija, Rajagopalan, Deepthi, Rehnström, Karola, Reichenberg, Abraham, Sabo, Aniko, Sachse, Michael, Sanders, Stephan J., Schafer, Chad, Schulte-Rüther, Martin, Skuse, David, Stevens, Christine, Szatmari, Peter, Tammimies, Kristiina, Valladares, Otto, Voran, Annette, Wang, Li-San, Weiss, Lauren A., Willsey, Jeremy A., Yu, Timothy W., Yuen, Ryan K. C., Cook, Edwin H., Freitag, Christine M., Gill, Michael, Hultman, Christina M., Lehner, Thomas, Palotie, Aarno, Schellenberg, Gerard D., Sklar, Pamela, State, Matthew W., Sutcliffe, James S., Walsh, Christopher A., Scherer, Stephen W., Zwick, Michael E., Barrett, Jeffrey C., Cutler, David J., Roeder, Kathryn, Devlin, Bernie, Daly, Mark J., and Buxbaum, Joseph D.

Published
2014
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37. DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

Author

van Dongen, Jenny, Hagenbeek, Fiona A., Suderman, Matthew, Roetman, Peter J., Sugden, Karen, Chiocchetti, Andreas G., Ismail, Khadeeja, Mulder, Rosa H., Hafferty, Jonathan D., Adams, Mark J., Walker, Rosie M., Morris, Stewart W., Lahti, Jari, Küpers, Leanne K., Escaramis, Georgia, Alemany, Silvia, Jan Bonder, Marc, Meijer, Mandy, Ip, Hill F., Jansen, Rick, Baselmans, Bart M. L., Parmar, Priyanka, Lowry, Estelle, Streit, Fabian, Sirignano, Lea, Send, Tabea S., Frank, Josef, Jylhävä, Juulia, Wang, Yunzhang, Mishra, Pashupati Prasad, Colins, Olivier F., Corcoran, David L., Poulton, Richie, Mill, Jonathan, Hannon, Eilis, Arseneault, Louise, Korhonen, Tellervo, Vuoksimaa, Eero, Felix, Janine F., Bakermans-Kranenburg, Marian J., Campbell, Archie, Czamara, Darina, Binder, Elisabeth, Corpeleijn, Eva, Gonzalez, Juan R., Grazuleviciene, Regina, Gutzkow, Kristine B., Evandt, Jorunn, Vafeiadi, Marina, Klein, Marieke, van der Meer, Dennis, Ligthart, Lannie, Heijmans, Bastiaan T., ’t Hoen, Peter A. C., van Meurs, Joyce, Franke, Lude, Boomsma, Dorret I., Pool, René, Hottenga, Jouke J., van Greevenbroek, Marleen M. J., Stehouwer, Coen D. A., van der Kallen, Carla J. H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Sasha, Tigchelaar, Ettje F., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, André G., Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Luijk, René, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik. W., ’t Hoen, Peter-Bram, Kluft, Cornelis, Davies, Gareth E., Hakulinen, Christian, Keltikangas-Järvinen, Liisa, Franke, Barbara, Freitag, Christine M., Konrad, Kerstin, Hervas, Amaia, Fernández-Rivas, Aranzazu, Vetro, Agnes, Raitakari, Olli, Lehtimäki, Terho, Vermeiren, Robert, Strandberg, Timo, Räikkönen, Katri, Snieder, Harold, Witt, Stephanie H., Deuschle, Michael, Pedersen, Nancy L., Hägg, Sara, Sunyer, Jordi, Kaprio, Jaakko, Ollikainen, Miina, Moffitt, Terrie E., Tiemeier, Henning, van IJzendoorn, Marinus H., Relton, Caroline, Vrijheid, Martine, Sebert, Sylvain, Jarvelin, Marjo-Riitta, Caspi, Avshalom, Evans, Kathryn L., McIntosh, Andrew M., Bartels, Meike, Child and Adolescent Psychiatry / Psychology, Pediatrics, Internal Medicine, Urology, Epidemiology, Orthopedics and Sports Medicine, Clinical Child and Family Studies, van der Kallen, Carla J. H., Schalkwijk, Casper G., Wijmenga, Cisca, Franke, Lude, Zhernakova, Sasha, Tigchelaar, Ettje F., Slagboom, P. Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H., van den Berg, Leonard H., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, André G., van Meurs, Joyce, Jhamai, P. Mila, Verbiest, Michael, Suchiman, H. Eka D., Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, Zhernakova, Dasha V., Jansen, Rick, van 't Hof, Peter, Deelen, Patrick, Nooren, Irene, 't Hoen, Peter A. C., Heijmans, Bastiaan T., Moed, Matthijs, Vermaat, Martijn, Luijk, René, Jan Bonder, Marc, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M., Swertz, Morris A., van Zwet, Erik W., 't Hoen, Peter-Bram, Boomsma, Dorret I., Pool, René, van Dongen, Jenny, Hottenga, Jouke J., van Greevenbroek, Marleen M. J., Stehouwer, Coen D. A., Institute for Molecular Medicine Finland, University of Helsinki, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Faculty of Medicine, Tellervo Korhonen / Principal Investigator, Genetic Epidemiology, Faculty Common Matters (Faculty of Medicine), Cognitive and Brain Aging, Helsinki Inequality Initiative (INEQ), Psychosocial factors and health, Faculty Common Matters (Faculty of Education), Medicum, HUS Internal Medicine and Rehabilitation, Timo Strandberg / Principal Investigator, Department of Medicine, Clinicum, Geriatrian yksikkö, Reproductive Origins of Adult Health and Disease (ROAHD), Life Course Epidemiology (LCE), Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Pediatric surgery, APH - Mental Health, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Methodology, Tampere University, Health Sciences, Department of Clinical Chemistry, Clinical Medicine, RS: MHeNs - R2 - Mental Health, and Psychiatrie & Neuropsychologie

Subjects
0301 basic medicine, Molecular biology, ADN, Physiology, CHILDREN, 3124 Neurology and psychiatry, Epigenesis, Genetic, Epigenome, 0302 clinical medicine, Child, RISK, ASSOCIATION, Middle Aged, Justice and Strong Institutions, Aggression, Psychiatry and Mental health, Schizophrenia, TWINS, Meta-analysis, Cord blood, Child, Preschool, DNA methylation, HEALTH, medicine.symptom, SMOKING, Adult, SDG 16 - Peace, Adolescent, 515 Psychology, Longevity, Biology, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Genetics, Humans, ddc:610, EXPOSURE, ABUSE, Genetic association, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], SDG 16 - Peace, Justice and Strong Institutions, 3112 Neurosciences, GENOME-WIDE, DNA Methylation, Epigenètica, medicine.disease, 3141 Health care science, 030104 developmental biology, COHORT PROFILE, 1182 Biochemistry, cell and molecular biology, CpG Islands, 3111 Biomedicine, Metaanàlisi, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Molecular psychiatry 26(6), 2148-2162 (2021). doi:10.1038/s41380-020-00987-x, Published by Macmillan, London

Published
2021

38. DNA methylation signatures of aggression and closely related constructs:A meta-analysis of epigenome-wide studies across the lifespan

Author

Hagenbeek, Fiona A., Suderman, Matthew, van Dongen, Jenny, Roetman, Peter J., Sugden, Karen, Chiocchetti, Andreas G., Ismail, Khadeeja, Mulder, Rosa H., Hafferty, Jonathan D., Adams, Mark J., Walker, Rosie M., Morris, Stewart W., Lahti, Jari, Küpers, Leanne K., Escaramis, Georgia, Alemany, Silvia, Jan Bonder, Marc, Meijer, Mandy, Ip, Hill F., Jansen, Rick, Baselmans, Bart M.L., Parmar, Priyanka, Lowry, Estelle, Streit, Fabian, Sirignano, Lea, Send, Tabea S., Frank, Josef, Jylhävä, Juulia, Wang, Yunzhang, Mishra, Pashupati Prasad, Colins, Olivier F., Felix, Janine F., Ligthart, Lannie, van Meurs, Joyce, Hottenga, Jouke J., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, André G., Verbiest, Michael, Verkerk, Marijn, van Rooij, Jeroen, van Dijk, Freerk, Tiemeier, Henning, van IJzendoorn, Marinus H., Bartels, Meike, Hagenbeek, Fiona A., Suderman, Matthew, van Dongen, Jenny, Roetman, Peter J., Sugden, Karen, Chiocchetti, Andreas G., Ismail, Khadeeja, Mulder, Rosa H., Hafferty, Jonathan D., Adams, Mark J., Walker, Rosie M., Morris, Stewart W., Lahti, Jari, Küpers, Leanne K., Escaramis, Georgia, Alemany, Silvia, Jan Bonder, Marc, Meijer, Mandy, Ip, Hill F., Jansen, Rick, Baselmans, Bart M.L., Parmar, Priyanka, Lowry, Estelle, Streit, Fabian, Sirignano, Lea, Send, Tabea S., Frank, Josef, Jylhävä, Juulia, Wang, Yunzhang, Mishra, Pashupati Prasad, Colins, Olivier F., Felix, Janine F., Ligthart, Lannie, van Meurs, Joyce, Hottenga, Jouke J., van Duijn, Cornelia M., Hofman, Bert A., Isaacs, Aaron, Uitterlinden, André G., Verbiest, Michael, Verkerk, Marijn, van Rooij, Jeroen, van Dijk, Freerk, Tiemeier, Henning, van IJzendoorn, Marinus H., and Bartels, Meike

Abstract

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 × 10−7; Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3–82%) of the aggression–methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

Published
2021

39. SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study

Author

Farrow, Elizabeth; https://orcid.org/0000-0003-0509-1637, Chiocchetti, Andreas G, Rogers, Jack C, Pauli, Ruth, Raschle, Nora M; https://orcid.org/0000-0002-3160-5999, González-Madruga, Karen; https://orcid.org/0000-0002-7586-7536, Smaragdi, Areti, Martinelli, Anne; https://orcid.org/0000-0002-7158-9778, Kohls, Gregor, Stadler, Christina; https://orcid.org/0000-0003-2178-0635, Konrad, Kerstin; https://orcid.org/0000-0001-9039-2615, Fairchild, Graeme, Freitag, Christine M; https://orcid.org/0000-0001-9676-4782, Chechlacz, Magdalena, De Brito, Stephane A; https://orcid.org/0000-0002-9082-6185, Farrow, Elizabeth; https://orcid.org/0000-0003-0509-1637, Chiocchetti, Andreas G, Rogers, Jack C, Pauli, Ruth, Raschle, Nora M; https://orcid.org/0000-0002-3160-5999, González-Madruga, Karen; https://orcid.org/0000-0002-7586-7536, Smaragdi, Areti, Martinelli, Anne; https://orcid.org/0000-0002-7158-9778, Kohls, Gregor, Stadler, Christina; https://orcid.org/0000-0003-2178-0635, Konrad, Kerstin; https://orcid.org/0000-0001-9039-2615, Fairchild, Graeme, Freitag, Christine M; https://orcid.org/0000-0001-9676-4782, Chechlacz, Magdalena, and De Brito, Stephane A; https://orcid.org/0000-0002-9082-6185

Abstract

Conduct disorder (CD), a psychiatric disorder characterized by a repetitive pattern of antisocial behaviors, results from a complex interplay between genetic and environmental factors. The clinical presentation of CD varies both according to the individual's sex and level of callous-unemotional (CU) traits, but it remains unclear how genetic and environmental factors interact at the molecular level to produce these differences. Emerging evidence in males implicates methylation of genes associated with socio-affective processes. Here, we combined an epigenome-wide association study with structural neuroimaging in 51 females with CD and 59 typically developing (TD) females to examine DNA methylation in relation to CD, CU traits, and gray matter volume (GMV). We demonstrate an inverse pattern of correlation between CU traits and methylation of a chromosome 1 region in CD females (positive) as compared to TD females (negative). The identified region spans exon 1 of the SLC25A24 gene, central to energy metabolism due to its role in mitochondrial function. Increased SLC25A24 methylation was also related to lower GMV in multiple brain regions in the overall cohort. These included the superior frontal gyrus, prefrontal cortex, and supramarginal gyrus, secondary visual cortex and ventral posterior cingulate cortex, which are regions that have previously been implicated in CD and CU traits. While our findings are preliminary and need to be replicated in larger samples, they provide novel evidence that CU traits in females are associated with methylation levels in a fundamentally different way in CD and TD, which in turn may relate to observable variations in GMV across the brain.

Published
2021

40. Risk stratification for bipolar disorder using polygenic risk scores among young high-risk adults

Author

Biere, Silvia, Kranz, Thorsten M., Matura, Silke, Petrova, Kristiyana, Streit, Fabian, Chiocchetti, Andreas G., Grimm, Oliver, Brum, Murielle, Brunkhorst-Kanaan, Natalie, Oertel, Viola, Malyshau, Aliaksandr, Pfennig, Andrea, Bauer, Michael, Schulze, Thomas G., Kittel-Schneider, Sarah, and Reif, Andreas

Subjects
ddc:150, ddc:610
Abstract

Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.

Published
2020

41. Energy Metabolism Disturbances in Cell Models of PARK2 CNV Carriers with ADHD

Author

Palladino, Viola Stella, Chiocchetti, Andreas G., Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Bruestle, Oliver, Guenther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, Kittel-Schneider, Sarah, Palladino, Viola Stella, Chiocchetti, Andreas G., Frank, Lukas, Haslinger, Denise, McNeill, Rhiannon, Radtke, Franziska, Till, Andreas, Haupt, Simone, Bruestle, Oliver, Guenther, Katharina, Edenhofer, Frank, Hoffmann, Per, Reif, Andreas, and Kittel-Schneider, Sarah

Abstract

The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.

Published
2020

42. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Satterstrom, F. Kyle, Kosmicki, Jack A., Wang, Jiebiao, Breen, Michael S., De Rubeis, Silvia, An, Joon Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S., Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E., Dias, Caroline, Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus C.Y., Chiocchetti, Andreas G., Chung, Brian H.Y., Coon, Hilary, Cuccaro, Michael L., Curró, Aurora, Dalla Bernardina, Bernardo, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Nordentoft, Merete, Werge, Thomas, Appadurai, Vivek, Bækvad-Hansen, Marie, Hansen, Christine S., Pedersen, Carsten Bøcker, Satterstrom, F. Kyle, Kosmicki, Jack A., Wang, Jiebiao, Breen, Michael S., De Rubeis, Silvia, An, Joon Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S., Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E., Dias, Caroline, Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus C.Y., Chiocchetti, Andreas G., Chung, Brian H.Y., Coon, Hilary, Cuccaro, Michael L., Curró, Aurora, Dalla Bernardina, Bernardo, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Nordentoft, Merete, Werge, Thomas, Appadurai, Vivek, Bækvad-Hansen, Marie, Hansen, Christine S., and Pedersen, Carsten Bøcker

Abstract

Large-scale sequencing of patients with autism allows identification of over 100 putative ASD-associated genes, the majority of which are neuronally expressed, and investigation of distinct genetic influences on ASD compared with other neurodevelopmental disorders.

Published
2020

43. Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

Author

Fundació La Marató de TV3, Fundación Alicia Koplowitz, Ministerio de Economía y Competitividad (España), National Health and Medical Research Council (Australia), European Commission, Generalitat de Catalunya, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Ministerio de Educación, Cultura y Deporte (España), Torrico, Bàrbara, Antón-Galindo, Ester, Fernández-Castillo, Noèlia, Rojo Francàs, Eva, Ghorbani, Sadaf, Pineda-Cirera, Laura, Hervás, Amaia, Rueda, Isabel, Moreno, Estefanía, Fullerton, Janice M., Casadó, Vicent, Buitelaar, Jan K., Rommelse, Nanda, Franke, Barbara, Reif, Andreas, Chiocchetti, Andreas G., Freitag, Christine, Kleppe, Rune, Haavit, Jan, Toma, Claudio, Cormand, Bru, Fundació La Marató de TV3, Fundación Alicia Koplowitz, Ministerio de Economía y Competitividad (España), National Health and Medical Research Council (Australia), European Commission, Generalitat de Catalunya, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Ministerio de Educación, Cultura y Deporte (España), Torrico, Bàrbara, Antón-Galindo, Ester, Fernández-Castillo, Noèlia, Rojo Francàs, Eva, Ghorbani, Sadaf, Pineda-Cirera, Laura, Hervás, Amaia, Rueda, Isabel, Moreno, Estefanía, Fullerton, Janice M., Casadó, Vicent, Buitelaar, Jan K., Rommelse, Nanda, Franke, Barbara, Reif, Andreas, Chiocchetti, Andreas G., Freitag, Christine, Kleppe, Rune, Haavit, Jan, Toma, Claudio, and Cormand, Bru

Abstract

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3 mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3 protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 107), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia

Published
2020

44. The role of rare compound heterozygous events in autism spectrum disorder

Author

TN groep Adan, CMM USEQ Facility, Cancer, Neurogenetica, Brain, Lin, Bochao Danae, Colas, Fabrice, Nijman, Isaac J., Medic, Jelena, Brands, William, Parr, Jeremy R., van Eijk, Kristel R., Klauck, Sabine M., Chiocchetti, Andreas G., Freitag, Christine M., Maestrini, Elena, Bacchelli, Elena, Coon, Hilary, Vicente, Astrid, Oliveira, Guiomar, Pagnamenta, Alistair T., Gallagher, Louise, Ennis, Sean, Anney, Richard, Bourgeron, Thomas, Luykx, Jurjen J., Vorstman, Jacob, TN groep Adan, CMM USEQ Facility, Cancer, Neurogenetica, Brain, Lin, Bochao Danae, Colas, Fabrice, Nijman, Isaac J., Medic, Jelena, Brands, William, Parr, Jeremy R., van Eijk, Kristel R., Klauck, Sabine M., Chiocchetti, Andreas G., Freitag, Christine M., Maestrini, Elena, Bacchelli, Elena, Coon, Hilary, Vicente, Astrid, Oliveira, Guiomar, Pagnamenta, Alistair T., Gallagher, Louise, Ennis, Sean, Anney, Richard, Bourgeron, Thomas, Luykx, Jurjen J., and Vorstman, Jacob

Published
2020

45. Energy Metabolism Disturbances in Cell Models of PARK2 CNV Carriers with ADHD

Author

Palladino, Viola Stella, primary, Chiocchetti, Andreas G., additional, Frank, Lukas, additional, Haslinger, Denise, additional, McNeill, Rhiannon, additional, Radtke, Franziska, additional, Till, Andreas, additional, Haupt, Simone, additional, Brüstle, Oliver, additional, Günther, Katharina, additional, Edenhofer, Frank, additional, Hoffmann, Per, additional, Reif, Andreas, additional, and Kittel-Schneider, Sarah, additional

Published
2020
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46. ADHD‐associated PARK2copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient‐derived cell lines

Author

Radtke, Franziska, Palladino, Viola Stella, McNeill, Rhiannon V., Chiocchetti, Andreas G., Haslinger, Denise, Leyh, Matthias, Gersic, Danijel, Frank, Markus, Grünewald, Lena, Klebe, Stephan, Brüstle, Oliver, Günther, Katharina, Edenhofer, Frank, Kranz, Thorsten M., Reif, Andreas, and Kittel‐Schneider, Sarah

Abstract

Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (PARK2) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with PARK2CNVs in human‐derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD PARK2deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without PARK2CNVs. The selected 10 genes of interest were associated with oxidative stress response (TP53, NQO1,and NFE2L2), ubiquitin pathway (UBE3A, UBB, UBC,and ATXN3) and with a function in mitochondrial quality control (PINK1, MFN2,and ATG5). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H‐quinone‐dehydrogenase 1 (NQO1) expression was significantly increased in PARK2CNV carriers. In a multivariate analysis, ubiquitin C (UBC) was significantly upregulated in fibroblasts of PARK2CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (NNAT) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine‐proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in PARK2CNV carriers compared to wildtype healthy controls and ADHD patients.

Published
2022
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47. Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults

Author

Biere, Silvia, primary, Kranz, Thorsten M., additional, Matura, Silke, additional, Petrova, Kristiyana, additional, Streit, Fabian, additional, Chiocchetti, Andreas G., additional, Grimm, Oliver, additional, Brum, Murielle, additional, Brunkhorst-Kanaan, Natalie, additional, Oertel, Viola, additional, Malyshau, Aliaksandr, additional, Pfennig, Andrea, additional, Bauer, Michael, additional, Schulze, Thomas G., additional, Kittel-Schneider, Sarah, additional, and Reif, Andreas, additional

Published
2020
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48. Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

Author

Torrico, Bàrbara, primary, Antón-Galindo, Ester, additional, Fernàndez-Castillo, Noèlia, additional, Rojo-Francàs, Eva, additional, Ghorbani, Sadaf, additional, Pineda-Cirera, Laura, additional, Hervás, Amaia, additional, Rueda, Isabel, additional, Moreno, Estefanía, additional, Fullerton, Janice M., additional, Casadó, Vicent, additional, Buitelaar, Jan K., additional, Rommelse, Nanda, additional, Franke, Barbara, additional, Reif, Andreas, additional, Chiocchetti, Andreas G., additional, Freitag, Christine, additional, Kleppe, Rune, additional, Haavik, Jan, additional, Toma, Claudio, additional, and Cormand, Bru, additional

Published
2020
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49. Episignatures stratifying ADNP syndrome show modest correlation with phenotype

Author

Breen, Michael S., primary, Garg, Paras, additional, Tang, Lara, additional, Mendonca, Danielle, additional, Levy, Tess, additional, Barbosa, Mafalda, additional, Arnett, Anne B, additional, Kurtz-Nelson, Evangeline, additional, Agolini, Emanuele, additional, Battaglia, Agatino, additional, Chiocchetti, Andreas G, additional, Freitag, Christine M, additional, Garcia-Alcon, Alicia, additional, Grammatico, Paola, additional, Hertz-Picciotto, Irva, additional, Ludena-Rodriguez, Yunin, additional, Moreno, Carmen, additional, Novelli, Antonio, additional, Parellada, Mara, additional, Pascolini, Giulia, additional, Tassone, Flora, additional, Grice, Dorothy E, additional, Bernier, Raphael A, additional, Kolevzon, Alexander, additional, Sharp, Andrew, additional, Buxbaum, Joseph D, additional, Siper, Paige M, additional, and De Rubeis, Silvia, additional

Published
2020
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50. Drug-Resistant Juvenile Myoclonic Epilepsy: Misdiagnosis of Progressive Myoclonus Epilepsy

Author

Martin, Sarah, Strzelczyk, Adam, Lindlar, Silvia, Krause, Kristina, Reif, Philipp Sebastian, Menzler, Katja, Chiocchetti, Andreas G., Rosenow, Felix, Knake, Susanne, Klein, Karl Martin, and Ferlazzo, Edoardo

Subjects
juvenile myoclonic epilepsy, Neurology, epilepsy, genetics, pharmacoresistance, ddc:610, Lafora disease, Neurology (clinical), Brief Research Report, progressive myoclonus epilepsy
Abstract

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.

Published
2019
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