Exome sequencing in sporadic cases of schizophrenia and functional studies identify 21 putative candidate genes for schizophrenia and establish the RGS12 gene as a strong candidate. M. Guipponi1, F. Santoni1, V. Setola2, E. Oestreich3, C. Gehrig1, M. Rotharmel4, M. Cuenca4, O. Guilin4, D. Dikeos5, G. Papadimitriou5, A. Méary6,7,8,9, F. Schürhoff6,7,8,9, S. Jamain6,7,8,9, M. Leboyer6,7,8,9, D. Rujescu10, A. Pulver11, S. Moy12, D. Campion4, A. Malafosse1, D. Siderovski2, S. E. Antonarakis1 1) Dept of Genetic Medecine and Development, University of Geneva Medical School and University Hospitals of Geneva, Switzerland; 2) Dept of Physiology and Pharmacology, West Virginia University School of Medecine, USA; 3) Pacific Northwest University of Health Sciences, USA; 4) Centre Hospitalier du Rouvray, Sotteville les Rouen et INSERM U 1079, France; 5) Athens University Medical School, 1st department of Psychiatry, Eginition Hospital, Greece; 6) Inserm U955, Psychiatrie Génétique, Créteil, France; 7) Université Paris Est, Faculté de Médecine, Créteil, France; 8) Chenevier - H. Mondor, Pôle de Psychiatrie, Créteil, France; 9) Fondation Fondamental, Créteil, France; 10) Division of Molecular and Clinical Neurobiology at the University of Munich, Germany; 11) Epidemiology and Genetics Program in Psychiatry, John Hopkins School of Medicine, USA; 12) Carolina Institute for Developmental Disabilities, University of North Carolina, USA.

   Schizophrenia is a severe, debilitating mental illness with a strong genetic component. Identification of the genetic factors related to schizophrenia has been challenging and its genetic architecture is still largely unknown. To evaluate the contribution of damaging de novo mutations to schizophrenia, we sequenced the exomes of 58 sporadic cases of schizophrenia and their healthy parents. Exomes were captured and sequenced using the Agilent and Illumina technologies, respectively and genetic variants were called using our analytical pipeline that integrates BWA, Samtools, Pindel2 and Annovar. We identified 55 validated de novo variants, 21 of which were predicted as deleterious including 16 missense, 2 conserved splice site, 2 nonsense mutations and 1 frameshift deletion. The observed exonic point mutation rate of 0.91 events per trio or 1.7 x 10-8 per base per generation and the non-synonymous to synonymous ratio of 2.25 did not differ from neutral expectations. We did not observe multiple independent de novo variants in the same gene in our cohort. However, when combined to the other studies (Girard et al. 2011; Xu et al. 2012), our data allowed the identification of a second proband carrying a missense de novo SNV in the RGS12 gene, a finding unlikely to have occurred by chance (Monte Carlo simulation; P<0.0001). To further explore a potential role for RGS12 in schizophrenia, homozygous Rgs12 knock-out mice were tested for sensorimotor gating capabilities as measured by prepulse inhibition of acoustic startle responses, one of the well-documented biological markers for schizophrenia in humans. Remarkably, these mice showed a significantly impaired sensorimotor gating when compared to wild-type and heterozygous mice indicating that Rgs12 may underlie certain aspects of schizophrenia pathogenesis. Overall, this study provides a list of 21 putative candidate genes for schizophrenia and establishes the RGS12 gene as a strong candidate.