Genetic pathways linking oxytocin-vasotocin hypothalamic subunits with metabolic/psychiatric traits
Poster No:
532
Submission Type:
Abstract Submission
Authors:
Alina Irene Sartorius1, Dennis Van der Meer2, Alexey Shadrin2,3, Jaroslav Rokicki4, Megan Campbell5,6, Adriano Winterton7, Ole Andreassen2,3, Emanuel Schwarz8, Terje Nærland3,9, Lars Westlye1,3, Daniel Quintana1,3,9
Institutions:
1Department of Psychology, University of Oslo, Oslo, Norway, 2Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 3K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo, Oslo, Norway, 4Centre of Research and Education in Forensic Psychiatry, Oslo University Hospital, Oslo, Norway, 5Child and Adolescent Health Unit, Department of Paediatrics, University of Cape Town, Cape Town, South Africa, 6Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health, Boston, MA, 7Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway, 8Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany, 9NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway, Oslo, Norway
First Author:
Co-Author(s):
Dennis Van der Meer
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo
Oslo, Norway
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo
Oslo, Norway
Alexey Shadrin
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Jaroslav Rokicki
Centre of Research and Education in Forensic Psychiatry, Oslo University Hospital
Oslo, Norway
Centre of Research and Education in Forensic Psychiatry, Oslo University Hospital
Oslo, Norway
Megan Campbell
Child and Adolescent Health Unit, Department of Paediatrics, University of Cape Town|Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health
Cape Town, South Africa|Boston, MA
Child and Adolescent Health Unit, Department of Paediatrics, University of Cape Town|Global Initiative for Neuropsychiatric Genetics Education in Research, Harvard T.H. Chan School of Public Health
Cape Town, South Africa|Boston, MA
Adriano Winterton
Department of Child Health and Development, Norwegian Institute of Public Health
Oslo, Norway
Department of Child Health and Development, Norwegian Institute of Public Health
Oslo, Norway
Ole Andreassen
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Centre for Precision Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Emanuel Schwarz
Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University
Mannheim, Germany
Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Heidelberg University
Mannheim, Germany
Terje Nærland
K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo|NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway
Oslo, Norway|Oslo, Norway
K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo|NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway
Oslo, Norway|Oslo, Norway
Lars Westlye
Department of Psychology, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Department of Psychology, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo
Oslo, Norway|Oslo, Norway
Daniel Quintana
Department of Psychology, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo|NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway
Oslo, Norway|Oslo, Norway|Oslo, Norway
Department of Psychology, University of Oslo|K.G. Jebsen Centre for Neurodevelopmental Disorders, Institute of clinical medicine, University of Oslo|NevSom, Department of Rare Disorders, Oslo University Hospital, Oslo, Norway
Oslo, Norway|Oslo, Norway|Oslo, Norway
Introduction:
The neuropeptides oxytocin (OT) and vasotocin (VT) are predominantly produced in the supraoptic and paraventricular nuclei of the anterior-inferior/-superior and the tubular-superior subunits of the hypothalamus(1,2; fig. 1), a subcortical structure coordinating various physiological functions (3). Evidence suggests that OT/VT and the hypothalamus are implicated in similar traits (4,5) and that genetic variants of the OT/VT systems may contribute to co-occurrences of metabolic and psychiatric conditions (6). Subcortical structures and metabolic/psychiatric traits are moderately to highly heritable (7,8,9). However, the genetic pathway underlying these metabolic/psychiatric traits and OT/VT hypothalamic subunits has not been clearly delineated. Leveraging recent advances in brain image segmentation and the availability of large imaging and genetic datasets, we identify the genetic overlap between the three hypothalamic volumes and psychiatric/metabolic traits associated with the OT/VT system.
·Fig. 1. The five subunits (three ROI in color) and the position of the two nuclei of interest (i.e., paraventricular and supraoptic; small areas shaded in dark grey) in the human hypothalamus.
Methods:
The hypothalamus was segmented into its five subunits with the automated hypothalamus segmentation tool from FreeSurfer. Subsequently, GWAS with the REGENIE tool were run on each of the three oxytocinergic-vasotocinergic hypothalamus subunits. Using the summary statistics from these GWASs and from ten selected metabolic and psychiatric traits (schizophrenia, bipolar disorder, autism, BMI, waist-to-hip ratio, HDL, LDL, systolic blood pressure, diabetes type II, bone mineral density) from published GWAS, we deployed bivariate mixture models ("MiXeR") and a conjunctional FDR approach to assess the pattern of genetic overlap and to identify specific loci shared between the three oxytocinergic-vasotocinergic hypothalamus subunits and ten metabolic and psychiatric traits related to oxytocin and vasotocin signaling. The identified loci were annotated with Open Targets Genetics and FUMA.
Results:
We show that the three subunits share small to moderate global genetic overlap with the ten tested traits (fig. 2). The proportion of genetic overlap between the subunits with the psychiatric traits on the one hand and metabolic traits on the other hand is similarly large. The tubular superior subunit generally shared more overlap with all traits than the two anterior subunits. With our local genetic overlap analyses, we pinpoint 78 unique loci jointly associated across all subunit and trait combinations. The genes associated with these loci were enriched in gene-sets linked to among other cognitive performance, cortical morphology measures and neuroticism, and the genes associated with the anterior-inferior subunit and the ten metabolic/psychiatric traits were up-regulated in female reproductive organs.
·Fig. 2. aiHyp/asHyp/tsHyp = hypothala. subunits, BD = Bipolar disorder, SCZ = Schizophrenia, BMD = Bone mineral density, SBP = Systolic blood pressure, T2D = diabetes type II, WHR = Waist-to-hip ratio
Conclusions:
This study advances our understanding of the genetic underpinnings of the three oxytocin-vasotocinergic hypothalamic subunits in relation to selected metabolic/psychiatric traits. We applied a novel approach on the subunit-level which allows for a more targeted investigation of the oxytocin-vasotocin system. We delineated and quantified the genetic overlap and pinpointed the SNPs that may constitute this genetic pathway, considering the specific oxytocin/vasotocin synthesis sites in the hypothalamus. This may point to a shared genetic architecture between these hypothalamic volumes and traits. The findings emphasize the polygenic architecture of the oxytocin/vasotocin hypothalamic subunits and health-relevant traits, such as schizophrenia and blood lipid levels. With the identified SNPs, we provide potential new avenues for future research and help shed light on the intricate role the oxytocinergic-vasotocinergic hypothalamus subunits may have in both mental and physical health.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Genetics:
Genetic Association Studies
Modeling and Analysis Methods:
Segmentation and Parcellation 2
Other Methods
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Subcortical Structures
Keywords:
Neurotransmitter
Psychiatric
Segmentation
STRUCTURAL MRI
Sub-Cortical
Systems
Other - Oxytocin, Genetic overlap, Metabolism
1|2Indicates the priority used for review
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