Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet Research article Genetic variants associated with psychotic symptoms across psychiatric disorders Marco Calabrò a , Stefano Porcelli b , Concetta Crisafulli a , Diego Albani c , Siegfried Kasper d , Joseph Zohar e , Daniel Souery f , Stuart Montgomery g , Vilma Mantovani h , Julien Mendlewicz i , Stefano Bonassi j,k , Eduard Vieta l , Alessandra Frustaci m , Giuseppe Ducci n , Stefano Landi o , Stefania Boccia p,q , Antonello Bellomo r , Marco Di Nicola s , Luigi Janiri t , Roberto Colombo u , Francesco Benedetti t , Laura Mandelli b , Chiara Fabbri b , Alessandro Serretti b, * a Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Italy b Department of Biomedical and NeuroMotor Sciences, University of Bologna, Italy c Laboratory of Biology of Neurodegenerative Disorders, Neuroscience Department, IRCCS Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy d Department of Psychiatry and Psychotherapy, Medical University Vienna, Austria e Department of Psychiatry, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Israel f Laboratoire de Psychologie Medicale, Universitè Libre de Bruxelles and Psy Pluriel, Centre Européen de Psychologie Medicale, Brussels, Belgium g lmperial College School of Medicine, London, UK h Center for Applied Biomedical Research (CRBA), St. Orsola University Hospital, Bologna, Italy i Université Libre de Bruxelles, Belgium j Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy k Department of Human Sciences and Quality of Life Promotion, San Raffaele University, Rome, Italy l Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain m Barnet, Enfield and Haringey Mental Health NHS Trust, St.Ann’s Hospital, St.Ann’s Road, N15 3 TH, London, UK n Mental Health Department, ASL Roma 1, Rome, Italy o Dipartimento di Biologia, Università di Pisa, Pisa, Italy p Sezione di Igiene, Istituto di Sanità Pubblica, Università Cattolica del Sacro Cuore, Roma, Italy q Department of Woman and Child Health and Public Health - Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy r Dipartimento di Medicina Clinica e Sperimentale, Foggia University, Italy s Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy t Faculty of Medicine "Agostino Gemelli", Catholic University of the Sacred Heart, Rome, Italy u Division of Neuroscience, IRCCS Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy ARTICLE INFO Keywords: CACNA1C Genetics Schizophrenia Depression Cross-disorder risk Symptom clusters ABSTRACT Background: Recent evidence suggests that psychiatric symptoms share a common genetic liability across di- agnostic categories. The present study investigated the effects of variants within previously identified relevant genes on specific symptom clusters, independently from the diagnosis. Methods: 1550 subjects affected by Schizophrenia (SCZ), Major Depressive Disorder or Bipolar Disorder were included. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Hamilton Depression Rating Scale (HDRS). Principal component analysis and a further clinical refinement were used to define symptom clusters. Clusters scores were tested for association with 46 genetic variants within nine genes previously linked to one or more major psychiatric disorders by large genome wide association studies (ANK3, CACNA1C, CACNB2, FKBP5, FZD3, GRM7, ITIH3, SYNE1, TCF4). Exploratory analyses were performed in each disorder separately to further elucidate the SNPs effects. Results: five PANSS clusters (Negative; Impulsiveness; Cognitive; Psychotic; Depressive) and four HDRS clusters (Core Depressive; Somatic; Psychotic-like; Insomnia) were identified. CACNA1C rs11615998 was associated with HDRS Psychotic cluster in the whole sample. In the SCZ sample, CACNA1C rs11062296 was associated with PANSS Impulsiveness cluster and CACNA1C rs2238062 was associated with PANSS negative cluster. Discussion: CACNA1C rs11615998 was associated with psychotic symptoms (C-allele carriers have decreased psychotic-risk) independently from the diagnosis, in line with the evidence of a cross disorder effect of many risk https://doi.org/10.1016/j.neulet.2020.134754 Received 19 September 2019; Received in revised form 6 December 2019; Accepted 11 January 2020 ⁎ Corresponding author at: Department of Biomedical and NeuroMotor Sciences, University of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy. E-mail address: alessandro.serretti@unibo.it (A. Serretti). Neuroscience Letters 720 (2020) 134754 Available online 13 January 2020 0304-3940/ © 2020 Elsevier B.V. All rights reserved. T