Affiliations 

  • 1 Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  • 2 The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai, China
  • 3 Department for Anesthesiology and Intensive Care, Faculty of Medicine, University of Leipzig, Leipzig, Germany
  • 4 School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
  • 5 Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany
  • 6 Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland
  • 7 Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
  • 8 Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
  • 9 Department of Biology, Animal Physiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
  • 10 Institute for Chemistry, Humboldt University, Berlin, Germany
  • 11 Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University of Erlangen- Nürnberg, Erlangen, Germany
  • 12 Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
  • 13 Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, Erlangen, Germany
  • 14 Centro Biologia Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain
  • 15 Life and Health Sciences Research Institute (ICVS), School of Medicine, Campus Gualtar, University of Minho, Braga, Portugal
  • 16 Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
  • 17 Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Christian.Mueller@uk-erlangen.de
Mol Psychiatry, 2021 Dec;26(12):7403-7416.
PMID: 34584229 DOI: 10.1038/s41380-021-01304-w

Abstract

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.