Overview | Research directions | Group members | Collaborations | Selected Publications

Overview

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.

Research directions

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.

Group members

  • Enrico Domenici, PI
  • Michele Filosi, postdoctoral fellow
  • ​Simone Montalbano, doctoral fellow
     
  • Giuseppe Fiorentino, PhD student
  • Stefania Mattevi, student

PhD positions are available. Motivated candidates, with interest in the application of large-scale genomic and computational approaches to understand brain function in health and disease, are encouraged to contact the PI.

Collaborations

  • 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
  • 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
  • Lucia Carboni, Department of Pharmacy and Biotechnology, University of Bologna, Italy
  • Carla Barbosa Nonino, Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto
  • Fondazione Italian Autism Network, Verona, Italy
  • Simons Foundation Autism Research Initiative (SFARI), Simons Foundation
  • Fondazione The Microsoft Research – University of Trento Centre for Computational and Systems Biology (COSBI)

Selected publications

Filosi M, Kam-Thong T, Essioux L, Muglia P, Trabetti E, Spooren W, Müller-Myshok B; Italian Autism Network, Domenici E. Transcriptome signatures from discordant sibling pairs reveal changes in peripheral blood immune cell composition in Autism Spectrum Disorder. Transl Psychiatry. 2020 10:106.

Marchetti L, Lauria M, Caberlotto L, Musazzi L, Popoli M, Mathé AA, Domenici E, Carboni L. Gene expression signature of antidepressant treatment response/non-response in Flinders Sensitive Line rats subjected to maternal separation. Eur Neuropsychopharmacol. 2020;31:69-85.

Misselbeck K, Parolo S*, Lorenzini F, Savoca V, Leonardelli L, Bora P, Morine MJ, Mione MC, Domenici E*, Priami C*. A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome. Nat Commun. 2019;10:5215.

Hoffman GE, Bendl J, Voloudakis G, Montgomery KS, Sloofman L, Wang YC, Shah HR, Hauberg ME, Johnson JS, Girdhar K, Song L, Fullard JF, Kramer R, Hahn CG, Gur R, Marenco S, Lipska BK, Lewis DA, Haroutunian V, Hemby S, Sullivan P, Akbarian S, Chess A, Buxbaum JD, Crawford GE, Domenici E, Devlin B, Sieberts SK, Peters MA, Roussos P. CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder. Sci Data. 2019;6:180.

Carboni L, McCarthy DJ, Delafont B, Filosi M, Ivanchenko E, Ratti E, Learned SM, Alexander R, Domenici E. Biomarkers for response in major depression: comparing paroxetine and venlafaxine from two randomised placebo-controlled clinical studies. Transl Psychiatry. 2019;9(1):182.

Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, Rajagopal VM, Als TD, T Nguyen H, Girdhar K, Boocock J, Roussos P, Fromer M, Kramer R, Domenici E, Gamazon ER, Purcell S; CommonMind Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; iPSYCH-GEMS Schizophrenia Working Group, Demontis D, Børglum AD, Walters JTR, O'Donovan MC, Sullivan P, Owen MJ, Devlin B, Sieberts SK, Cox NJ, Im HK, Sklar P, Stahl EA. Gene expression imputation across multiple brain regions provides insights into schizophrenia risk. Nat Genet. 2019;51:659-674.

Muglia P, Filosi M, Da Ros L, Kam-Thong T, Nardocci F, Trabetti E, Ratti E, Rizzini P, Zuddas A, Bernardina BD, Italian Autism Network, Domenici E. The Italian autism network (ITAN): a resource for molecular genetics and biomarker investigations. BMC Psychiatry. 2018;18(1):369.

Dobbyn A, Huckins LM, Boocock J, Sloofman LG, Glicksberg BS, Giambartolomei C, Hoffman GE, Perumal TM, Girdhar K, Jiang Y, Raj T, Ruderfer DM, Kramer RS, Pinto D; CommonMind Consortium, Akbarian S, Roussos P, Domenici E, Devlin B, Sklar P, Stahl EA, Sieberts SK. Landscape of Conditional eQTL in Dorsolateral Prefrontal Cortex and Co-localization with Schizophrenia GWAS. Am J Hum Genet. 2018;102:1169-1184.

Hauberg ME, Fullard JF, Zhu L, Cohain AT, Giambartolomei C, Misir R, Reach S, Johnson JS, Wang M, Mattheisen M, Børglum AD, Zhang B, Sieberts SK, Peters MA, Domenici E, Schadt EE, Devlin B, Sklar P, Roeder K, Roussos P; CommonMind Consortium. Differential activity of transcribed enhancers in the prefrontal cortex of 537 cases with schizophrenia and controls. Mol Psychiatry. 2019; 24:1685-1695.

Domenici E. Schizophrenia genetics comes to translation. NPJ Schizophr. 2017; 3:10.

Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, Ruderfer DM, Oh EC, Topol A, Shah HR, Klei LL, Kramer R, Pinto D, Gümüş ZH, Cicek AE, Dang KK, Browne A, Lu C, Xie L, Readhead B, Stahl EA, Xiao J, Parvizi M, Hamamsy T, Fullard JF, Wang YC, Mahajan MC, Derry JM, Dudley JT, Hemby SE, Logsdon BA, Talbot K, Raj T, Bennett DA, De Jager PL, Zhu J, Zhang B, Sullivan PF, Chess A, Purcell SM, Shinobu LA, Mangravite LM, Toyoshiba H, Gur RE, Hahn CG, Lewis DA, Haroutunian V, Peters MA, Lipska BK, Buxbaum JD, Schadt EE, Hirai K, Roeder K, Brennand KJ, Katsanis N, Domenici E, Devlin B, Sklar P. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016; 19:1442-1453. 

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.