Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
Richard Dear
Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
Rafael Romero-Garcia
Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Medical Physiology and Biophysics, Instituto deBiomedicina de Sevilla (IBiS) HUVR/CSIC Universidad de Sevilla/CIBERSAM, ISCIII, Sevilla, Spain
Varun Warrier
Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom; Department of Psychology, University of Cambridge, Cambridge, United States
Jakob Seidlitz
Lifespan Brain Institute, The Children’s Hospital of Philadelphia and Penn Medicine, Philadelphia, United States; Department of Child and Adolescent Psychiatry and Behavioral Science,The Children’s Hospital of Philadelphia, Philadelphia, United States; Department of Psychiatry, University of Pennsylvania, Philadelphia, United States
Ottavia Dipasquale
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
Federico Turkheimer
Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
The relationship between obesity and human brain structure is incompletely understood. Using diffusion-weighted MRI from ∼30,000 UK Biobank participants, we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal/temporal/striatal system associated with ISOVF and a medial temporal/occipital/striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9×10−4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (P<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.
