TY - JOUR A1 - Rivero, Olga A1 - Reif, Andreas A1 - Sanjuan, Julio A1 - Molto, Maria D. A1 - Kittel-Schneider, Sarah A1 - Najera, Carmen A1 - Toepner, Theresia A1 - Lesch, Klaus-Peter T1 - Impact of the AHI1 Gene on the Vulnerability to Schizophrenia: A Case-Control Association Study N2 - Background: The Abelson helper integration-1 (AHI1) gene is required for both cerebellar and cortical development in humans. While the accelerated evolution of AHI1 in the human lineage indicates a role in cognitive (dys)function, a linkage scan in large pedigrees identified AHI1 as a positional candidate for schizophrenia. To further investigate the contribution of AHI1 to the susceptibility of schizophrenia, we evaluated the effect of AHI1 variation on the vulnerability to psychosis in two samples from Spain and Germany. Methodology/Principal Findings: 29 single-nucleotide polymorphisms (SNPs) located in a genomic region including the AHI1 gene were genotyped in two samples from Spain (280 patients with psychotic disorders; 348 controls) and Germany (247 patients with schizophrenic disorders; 360 controls). Allelic, genotypic and haplotype frequencies were compared between cases and controls in both samples separately, as well as in the combined sample. The effect of genotype on several psychopathological measures (BPRS, KGV, PANSS) assessed in a Spanish subsample was also evaluated. We found several significant associations in the Spanish sample. Particularly, rs7750586 and rs911507, both located upstream of the AHI1 coding region, were found to be associated with schizophrenia in the analysis of genotypic (p = 0.0033, and 0.031,respectively) and allelic frequencies (p = 0.001 in both cases). Moreover, several other risk and protective haplotypes were detected (0.006,p,0.036). Joint analysis also supported the association of rs7750586 and rs911507 with the risk for schizophrenia. The analysis of clinical measures also revealed an effect on symptom severity (minimum P value = 0.0037). Conclusions/Significance: Our data support, in agreement with previous reports, an effect of AHI1 variation on the susceptibility to schizophrenia in central and southern European populations. KW - Schizophrenie KW - Abelson helper integration-1 (AHI1) Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68501 ER - TY - JOUR A1 - Rivero, Olga A1 - Alhama-Riba, Judit A1 - Ku, Hsing-Ping A1 - Fischer, Matthias A1 - Ortega, Gabriela A1 - Álmos, Péter A1 - Diouf, David A1 - van den Hove, Daniel A1 - Lesch, Klaus-Peter T1 - Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation JF - Frontiers in Genetics N2 - Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity. KW - sialyltransferase KW - sialic acid KW - psychiatric disorders KW - attention-deficit/hyperactivity disorder (ADHD) KW - prefrontal cortex KW - hippocampus KW - mouse model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246855 SN - 1664-8021 VL - 12 ER - TY - JOUR A1 - Brevik, Erlend J A1 - van Donkelaar, Marjolein M. J. A1 - Weber, Heike A1 - Sánchez-Mora, Cristina A1 - Jacob, Christian A1 - Rivero, Olga A1 - Kittel-Schneider, Sarah A1 - Garcia-martinez, Iris A1 - Aebi, Marcel A1 - van Hulzen, Kimm A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep A A1 - Lesch, Klaus-Peter A1 - Reif, Andreas A1 - Ribases, Marta A1 - Franke, Barbara A1 - Posserud, Maj-Britt A1 - Johansson, Stefan A1 - Lundervold, Astri J. A1 - Haavik, Jan A1 - Zayats, Tetyana T1 - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder JF - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics N2 - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. KW - Large multicenter ADHD KW - Antisocial behavior KW - Diagnostic approach KW - Rating scale KW - Gene KW - Deficit/hyperactivity disorder KW - Susceptibility loci KW - Conduct disorder KW - Association KW - Adult KW - ADHD KW - Aggression KW - GWAS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116 VL - 171B IS - 5 ER - TY - JOUR A1 - Vitale, Maria Rosaria A1 - Zöller, Johanna Eva Maria A1 - Jansch, Charline A1 - Janz, Anna A1 - Edenhofer, Frank A1 - Klopocki, Eva A1 - van den Hove, Daniel A1 - Vanmierlo, Tim A1 - Rivero, Olga A1 - Kasri, Nael Nadif A1 - Ziegler, Georg Christoph A1 - Lesch, Klaus-Peter T1 - Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9 JF - Stem Cell Research N2 - Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13\(^{+/-}\)) and a CDH13 null mutant (CDH13\(^{-/-}\)) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype. KW - CRISPR-Cas Systems KW - cadherins KW - female KW - heterozygote KW - humans KW - Induced Pluripotent Stem Cells KW - middle aged KW - neurodevelopmental disorders / genetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260331 VL - 51 ER - TY - JOUR A1 - Ferero, Andrea A1 - Rivero, Olga A1 - Wäldchen, Sina A1 - Ku, Hsing-Ping A1 - Kiser, Dominik P. A1 - Gärtner, Yvonne A1 - Pennington, Laura S. A1 - Waider, Jonas A1 - Gaspar, Patricia A1 - Jansch, Charline A1 - Edenhofer, Frank A1 - Resink, Thérèse J. A1 - Blum, Robert A1 - Sauer, Markus A1 - Lesch, Klaus-Peter T1 - Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain JF - Frontiers in Cellular Neuroscience N2 - Background: During early prenatal stages of brain development, serotonin (5-HT)-specific neurons migrate through somal translocation to form the raphe nuclei and subsequently begin to project to their target regions. The rostral cluster of cells, comprising the median and dorsal raphe (DR), innervates anterior regions of the brain, including the prefrontal cortex. Differential analysis of the mouse 5-HT system transcriptome identified enrichment of cell adhesion molecules in 5-HT neurons of the DR. One of these molecules, cadherin-13 (Cdh13) has been shown to play a role in cell migration, axon pathfinding, and synaptogenesis. This study aimed to investigate the contribution of Cdh13 to the development of the murine brain 5-HT system. Methods: For detection of Cdh13 and components of the 5-HT system at different embryonic developmental stages of the mouse brain, we employed immunofluorescence protocols and imaging techniques, including epifluorescence, confocal and structured illumination microscopy. The consequence of CDH13 loss-of-function mutations on brain 5-HT system development was explored in a mouse model of Cdh13 deficiency. Results: Our data show that in murine embryonic brain Cdh13 is strongly expressed on 5-HT specific neurons of the DR and in radial glial cells (RGCs), which are critically involved in regulation of neuronal migration. We observed that 5-HT neurons are intertwined with these RGCs, suggesting that these neurons undergo RGC-guided migration. Cdh13 is present at points of intersection between these two cell types. Compared to wildtype controls, Cdh13-deficient mice display increased cell densities in the DR at embryonic stages E13.5, E17.5, and adulthood, and higher serotonergic innervation of the prefrontal cortex at E17.5. Conclusion: Our findings provide evidence for a role of CDH13 in the development of the serotonergic system in early embryonic stages. Specifically, we indicate that Cdh13 deficiency affects the cell density of the developing DR and the posterior innervation of the prefrontal cortex (PFC), and therefore might be involved in the migration, axonal outgrowth and terminal target finding of DR 5-HT neurons. Dysregulation of CDH13 expression may thus contribute to alterations in this system of neurotransmission, impacting cognitive function, which is frequently impaired in neurodevelopmental disorders including attention-deficit/hyperactivity and autism spectrum disorders. KW - serotonin KW - cadherin-13 (CDH13) KW - T-cadherin KW - neurodevelopment KW - psychiatric disorders KW - radial glia KW - dorsal raphe KW - prefrontal cortex Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170313 VL - 11 IS - 307 ER - TY - JOUR A1 - Drgonova, Jana A1 - Walther, Donna A1 - Hartstein, G Luke A1 - Bukhari, Mohammad O A1 - Baumann, Michael H A1 - Katz, Jonathan A1 - Hall, F Scott A1 - Arnold, Elizabeth R A1 - Flax, Shaun A1 - Riley, Anthony A1 - Rivero, Olga A1 - Lesch, Klaus-Peter A1 - Troncoso, Juan A1 - Ranscht, Barbara A1 - Uhl, George R T1 - Cadherin 13: Human cis-Regulation and Selectively Altered Addiction Phenotypes and Cerebral Cortical Dopamine in Knockout Mice JF - Molecular Medicine N2 - The Cadherin 13 (CDH13) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD. KW - Cadherin (CDH13) KW - CDH13 mRNA KW - Attention Deficit Hyperactivity Disorder (ADHD) KW - CDH13 Expression KW - Human CDH13 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165842 VL - 22 ER -