Corrado Sandini1, Maëlle Chambaz2, Maude Schneider3, Marco Armando2, Daniela Zöller4, Marie Schaer2, Carmen Sandi5, Dimitri Van De Ville6, Stephan Eliez7. 1. Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland. Electronic address: Corrado.Sandini@unige.ch. 2. Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland. 3. Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Center for Contextual Psychiatry, Research Group Psychiatry, Department of Neuroscience, KU Leuven, Leuven, Belgium. 4. Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 5. Brain Mind Institute, School of Life Sciences, École Polytechnique Federale de Lausanne, Lausanne, Switzerland. 6. Department of Radiology and Medical Informatics, University of Geneva, Switzerland; Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. 7. Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva School of Medicine, Geneva, Switzerland.
Abstract
BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) confers strongly increased genetic risk for multiple psychiatric disorders. Similarly to the general population, rates of psychiatric comorbidity suggest that common disease mechanisms are shared across dimensions of psychopathology. Such pleiotropic disease mechanisms remain however currently unknown. We hypothesized that pituitary dysmaturation, indicative of HPA-axis dysregulation, could correlate to reduced tolerance to daily life stressors and reflect pleiotropic risk factor for psychopathology. Moreover HPA-axis dysregulation could affect atypical cortical and hippocampal development previously described in 22q11DS. METHODS: Pituitary volume, hippocampal volume and cortical thickness measures were obtained from T1-weighted MRI images in a large longitudinal cohort of youth with 22q11DS (115 subjects, 260 scans, age-range = 5.4-31.6) and healthy controls (151 subjects, 280 scans, age-range = 5.1-32.3). We explored effects of pituitary dysmaturation on tolerance to stress, psychopathology and neurodevelopment employing mixed-models linear regression. Associations of pituitary and cortical development were correlated with the expression pattern of glucocorticoid receptor gene NR3C1 obtained from the Allen-Human-Brain-Atlas. RESULTS: We observed aberrant pituitary developmental trajectories in 22q11DS, with volumetric reductions emerging by young-adulthood (P = 0.0006). Longitudinal pituitary decline was associated with to reduced tolerance to stress (P = 0.04), higher overall psychopathology (P = 0.0003) and increased risk of psychiatric comorbidity (P = 0.02). Moreover, pituitary decline correlated with blunted growth of the right hippocampus (P = 0.03) and to increased cortical thinning of mostly temporal and orbitofrontal regions mediated by NR3C1 gene expression. CONCLUSION: Atypical pituitary development could reflect progressive extinction of HPAA due to chronic hyper-activation, in agreement with existing biochemical evidence in 22q11DS. HPAA dysregulation could represent and endophenotype that confers pleiotropic vulnerability to psychopathology and atypical neurodevelopment in 22q11DS.
BACKGROUND: 22q11.2 Deletion Syndrome (22q11DS) confers strongly increased genetic risk for multiple psychiatric disorders. Similarly to the general population, rates of psychiatric comorbidity suggest that common disease mechanisms are shared across dimensions of psychopathology. Such pleiotropic disease mechanisms remain however currently unknown. We hypothesized that pituitary dysmaturation, indicative of HPA-axis dysregulation, could correlate to reduced tolerance to daily life stressors and reflect pleiotropic risk factor for psychopathology. Moreover HPA-axis dysregulation could affect atypical cortical and hippocampal development previously described in 22q11DS. METHODS: Pituitary volume, hippocampal volume and cortical thickness measures were obtained from T1-weighted MRI images in a large longitudinal cohort of youth with 22q11DS (115 subjects, 260 scans, age-range = 5.4-31.6) and healthy controls (151 subjects, 280 scans, age-range = 5.1-32.3). We explored effects of pituitary dysmaturation on tolerance to stress, psychopathology and neurodevelopment employing mixed-models linear regression. Associations of pituitary and cortical development were correlated with the expression pattern of glucocorticoid receptor gene NR3C1 obtained from the Allen-Human-Brain-Atlas. RESULTS: We observed aberrant pituitary developmental trajectories in 22q11DS, with volumetric reductions emerging by young-adulthood (P = 0.0006). Longitudinal pituitary decline was associated with to reduced tolerance to stress (P = 0.04), higher overall psychopathology (P = 0.0003) and increased risk of psychiatric comorbidity (P = 0.02). Moreover, pituitary decline correlated with blunted growth of the right hippocampus (P = 0.03) and to increased cortical thinning of mostly temporal and orbitofrontal regions mediated by NR3C1 gene expression. CONCLUSION: Atypical pituitary development could reflect progressive extinction of HPAA due to chronic hyper-activation, in agreement with existing biochemical evidence in 22q11DS. HPAA dysregulation could represent and endophenotype that confers pleiotropic vulnerability to psychopathology and atypical neurodevelopment in 22q11DS.
Authors: Corrado Sandini; Daniela Zöller; Maude Schneider; Anjali Tarun; Marco Armando; Barnaby Nelson; Paul G Amminger; Hok Pan Yuen; Connie Markulev; Monica R Schäffer; Nilufar Mossaheb; Monika Schlögelhofer; Stefan Smesny; Ian B Hickie; Gregor Emanuel Berger; Eric Yh Chen; Lieuwe de Haan; Dorien H Nieman; Merete Nordentoft; Anita Riecher-Rössler; Swapna Verma; Andrew Thompson; Alison Ruth Yung; Patrick D McGorry; Dimitri Van De Ville; Stephan Eliez Journal: Elife Date: 2021-09-27 Impact factor: 8.140