Neuropsychiatric diseases are highly heterogeneous and complex disorders, resulting from the interplay between environmental factors and multiple risk factors. In most cases, many genes contribute to the disease pathophysiology due to functional variants undermining key brain-related molecular pathways and circuits. Large scale genomic approaches are showing their potential to identify the key genetic determinants of neuropsychiatric disorders and highlight putative functional mechanisms underlying disease susceptibility. By combining genomic and proteomic approaches in diseased tissues, it is possible to search for biomarker fingerprints that may help disentangling the biological complexity of brain diseases and identifying patient subgroups that are homogeneous in terms of prognosis and drug response.
Genetic biomarkers: one of our main interests is the understanding of the contribution of common and rare variants to the risk of neuropsychiatric disorders as well as to intermediate phenotypes. Large scale collaborative efforts such as the Psychiatry Genomics Consortium (PGC) are helping unraveling the complexity of disorders such as schizophrenia, with more than hundred loci contributing to disease susceptibility. Thanks to consortium membership, and in collaboration with PCG members, we are investigating the association between risk variants and molecular or clinical phenotypes.
Functional genomics: we are investigating the genetic control of gene expression in the brain as a way to elucidate the genetic basis of CNS disorders at molecular level. By intersecting transcriptomics and data derived from large scale genetic association studies, it is possible to identify causal candidates among the regulatory variants that modulate gene expression (eQTLs). We are collaborating with the CommonMind Consortium (www.commonmind.org), a public-private effort aimed at generating and analyzing large-scale genomic data from human subjects with neuropsychiatric disorders.
Linking Peripheral and Central Biomarkers: given the evidence of cross-talk between the brain and peripheral systems, we are engaged in the search for non-invasive biomarkers that may help reducing the phenotypic complexity of neuropsychiatric disorders such as depression, schizophrenia and autism, and help stratifying patients into more biologically homogeneous subtypes. In this context, proteomic and genomic tools are expanding by orders of magnitude the number of testable hypothesis and allowing for the identification of molecular signatures rather than single markers. In order to establish correlations between peripheral and central markers, as well as between preclinical and clinical biomarkers, we are pursuing research efforts both in disease collections and in translational models of disease.
- Enrico Domenici, PI
- Roberto Visintainer, postdoctoral fellow
- Michele Filosi, postdoctoral fellow
- Daniela Calini, postdoctoral fellow
PhD positions are available. Motivated candidates, with interest in the application of large-scale genomic approaches to understand brain function in health and disease, are encouraged to contact the PI.
- Alessandro Bertolino, Giulio Pergola, Psychiatric Neuroscience Group, University of Bari, Italy
- Dheeraj Malhotra, Neuroscience Discovery, Roche, Basel, Switzerland
- Pat Sullivan, Departments of Genetics and Psychiatry, University of North Carolina at Chapel Hill, USA and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Sweden, and the Psychiatry Genomics Consortium
- Pam Sklar, Menachem Fromer, Panos Roussos, Division of Psychiatric Genomics, Mount Sinai, NY, USA and the CommonMind Consortium
- Mette Peters and Solly Sieberts, Sage Bionetworks, Seattle, USA
- Sven Cichon, Division of Human Genetics, University Hospital Basel, Switzerland
- Dan Rujescu, Department of Psychiatry, Psychotherapy and Psychosomatics, University of Halle, Germany
- Thomas Schulze, Institute of Psychiatric Phenomics and Genomics, University of Munich, Germany
- Lucia Carboni, Department of Pharmacy and Biotechnology, University of Bologna, Italy
- Fondazione Italian Autism Network, Verona, Italy
Fremer M, Roussos P, Sieberts S et al, Domenici E, Devlin E, Pamela S. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nature Neuroscience, in press.
Schubert CR, O'Donnell P, Quan J, Wendland JR, Xi HS, Winslow AR, Domenici E, et al. BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders. Neuron 2015: 88:1078-83
Carboni L, Domenici E. Proteome effects of antipsychotic drugs: Learning from preclinical models. Proteomics Clin Appl. 2015 Nov 9.
Schizophrenia Working Group of the Psychiatric Genomics (Domenici E among PIs). Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511:421-7
Malki K, Keers R, Tosto MG, Lourdusamy A, Carboni L, Domenici E, Uher R, McGuffin P, Schalkwyk LC. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder. BMC Med. 2014;12:73
Deng J, Lamb JR, Mckeown AP , Miller S, Muglia P, Guest PC, Bahn S, Domenici E, Rahmoune H. Identification of altered dipeptidyl-peptidase activities as potential biomarkers for unipolar depression. J. Affective Dis . 2013; 151:667-72.
Tansey KE, Guipponi M, Hu X, Domenici E, Lewis G, Malafosse A, Wendland JR, Lewis CM, McGuffin P, Uher R. Contribution of common genetic variants to antidepressant response. Biol Psychiatry 2013;73:679-82.
Tansey KE, Guipponi M, Perroud N, Bondolfi G, Domenici E et al. Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. PLoS Med. 2012; 9:e1001326.
Razzoli M, Domenici E, Carboni L, Rantamaki T, Lindholm J, Castrén E, Arban R. A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress. Genes Brain Behav. 2011; 10:424-33.
Kas MJ, Krishnan V, Gould TD, Collier DA, Olivier B, Lesch KP, Domenici E, Fuchs E, Gross C, Castrén E. Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders. Eur Neuropsychopharmacol. 2011; 21:532-44.
Piubelli C, Gruber S, El Khoury A, Mathé AA, Domenici E, Carboni L. Nortriptyline influences protein pathways involved in carbohydrate metabolism and actin-related processes in a rat gene-environment model of depression. Eur Neuropsychopharmacol.2011; 21:545-62.
Piubelli C, Carboni L, Becchi S, Mathé AA, Domenici E. Regulation of cytoskeleton machinery, neurogenesis and energy metabolism pathways in a rat gene-environment model of depression revealed by proteomic analysis. Neuroscience 2011; 176:349-80.
Piubelli C, Vighini M, Mathé AA, Domenici E, Carboni L. Escitalopram modulates neuron-remodelling proteins in a rat gene-environment interaction model of depression as revealed by proteomics. Part I: genetic background. Int J Neuropsychopharmacol. 2011; 14:796-833.
Cazzin C, Mion S, Caldara F, Rimland JM, Domenici E. Microarray analysis of cultured rat hippocampal neurons treated with brain derived neurotrophic factor. Mol Biol Rep. 2011; 38:983-90.
Blaveri E, Kelly F, Mallei A, Harris K, Taylor A, Reid J, Razzoli M, Carboni L, Piubelli C, Musazzi L, Racagni G, Mathé A, Popoli M, Domenici E, Bates S. Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours. PLoS One. 2010; 5:e12596.
Carboni L, Becchi S, Piubelli C, Mallei A, Giambelli R, Razzoli M, Mathé AA, Popoli M, Domenici E. Early-life stress and antidepressants modulate peripheral biomarkers in a gene-environment rat model of depression. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1037-48.
Domenici E, Willé D, Tozzi F, Prokopenko I, Miller S, McKeown A, Brittain C, Rujescu D, Giegling I, Turck CW, Holsboer F, Bullmore ET, Middleton L, Merlo-Pich E, Alexander RC, Muglia P. Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One 2010; 5:e9166.
Zambello E, Fuchs E, Abumaria N, Rygula R, Domenici E, Caberlotto L. Chronic psychosocial stress alters NPY system: Different effects in rat and tree shrew. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:122-30.
Muglia P, Tozzi F, Galwey NW, Francks C, Upmanyu R, Kong XQ, Antoniades A, Domenici E et al. Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry 2010; 15:589-601.
Cecconi D, Tessari M, Willé DR, Zoli M, Domenici E, Righetti PG, Carboni L. Serum proteomic analysis during nicotine self-administration, extinction and relapse in rats. Electrophoresis 2008; 29: 1525-33.
Domenici E, Muglia P. The search for peripheral disease markers in psychiatry by genomic and proteomic. Expert Opin Med Diagn. 2007; 1:235-51.
Czéh B, Müller-Keuker JI, Rygula R, Abumaria N, Hiemke C, Domenici E, Fuchs E. Chronic social stress inhibits cell proliferation in the adult medial prefrontal cortex: hemispheric asymmetry and reversal by fluoxetine treatment. Neuropsychopharmacology 2007: 32:1490-503.
Salaria S, Chana G, Caldara F, Feltrin E, Altieri M, Faggioni F, Domenici E, Merlo-Pich E, Everall IP. Microarray analysis of cultured human brain aggregates following cortisol exposure: Implications for cellular functions relevant to mood disorders. Neurobiol Dis. 2006; 23: 630-6.
Carboni L, Vighini M, Piubelli C, Castelletti L, Milli A, Domenici E. Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists. Eur Neuropsychopharmacol. 2006; 16: 521-3.
Carboni L, Piubelli C, Pozzato C, Astner H, Arban R, Righetti PG, Hamdan M, Domenici E. Proteomic analysis of rat hippocampus after repeated psychosocial stress. Neuroscience 2006; 137: 1237-46.
Piubelli C, Cecconi D, Astner H, Caldara F, Tessari M, Carboni L, Righetti PG, Domenici E. Proteomic changes in rat serum, polymorphonuclear and mononuclear leukocytes after chronic nicotine administration. Proteomics 2005; 5:1382-94.
Marengo E, Robotti E, Gianotti V, Righetti PG, Cecconi D, Domenici E. A new integrated statistical approach to the diagnostic use of two-dimensional maps. Electrophoresis 2003; 24:225-36.