title: Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis.
abstract: Reelin (RELN) is identified as a risk gene for major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD). However, the role of its downstream signaling molecule, the low-density lipoprotein receptor-related protein 8 (LRP8) in these illnesses is still unclear. To detect whether LRP8 is a susceptibility gene for SCZ and BPD, we analyzed the associations of single nucleotide polymorphisms (SNPs) in LRP8 in a total of 47,187 subjects (including 9379 SCZ patients; 6990 BPD patients; and 12,556 controls in a screening sample, and 1397 SCZ families, 3947 BPD patients, and 8387 controls in independent replications), and identified a non-synonymous SNP rs5174 in LRP8 significantly associated with SCZ and BPD as well as the combined psychosis phenotype (Pmeta= 1.99 × 10-5, odds ratio (OR) = 1.066, 95 % confidence interval (CI) = 1.035-1.098). The risk SNP rs5174 was also associated with LRP8 messenger RNA (mRNA) expression in multiple brain tissues across independent samples (lowest P = 0.00005). Further exploratory analysis revealed that LRP8 was preferentially expressed in fetal brain tissues. Protein-protein interaction (PPI) analysis demonstrated that LRP8 significantly participated in a highly interconnected PPI network build by top risk genes for SCZ and BPD (P = 7.0 × 10-4). Collectively, we confirmed that LRP8 is a risk gene for psychosis, and our results provide useful information toward a better understanding of genetic mechanism involving LRP8 underlying risk of complex psychiatric disorders.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. limingkiz@gmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Huang
authors.affiliation: Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania. maria.serbanescu@googlemail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Grigoroiu-Serbanescu
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bergen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Forstner
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Strohmaier
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Hecker
authors.affiliation: Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: School of Psychiatry, University of New South Wales, Sydney, Australia.|Black Dog Institute, Sydney, Australia.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Mitchell
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, D-52425, Jülich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Alkelai
authors.affiliation: Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lerer
authors.affiliation: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Fondation Fondamental, Créteil, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jamain
authors.affiliation: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.affiliation: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.|AP-HP, Groupe hospitalier Lariboisière - F. Widal, Pôle de Psychiatrie, Paris, France.|Université Paris Diderot, Paris, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bellivier
authors.affiliation: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Etain
authors.affiliation: Fondation Fondamental, Créteil, France.|Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d'Arc, Toul, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kahn
authors.affiliation: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Université Paris Est, Faculté de Médecine, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Henry
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D001921:Brain / Q000473:pathology; D002877:Chromosomes, Human / Q000235:genetics; D005333:Fetus / Q000473:pathology; D020869:Gene Expression Profiling; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D013997:Time Factors
chemical_list: D026502:LDL-Receptor Related Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C000717127:RELN protein, human
keywords: Bipolar disorder; LRP8; Schizophrenia; mRNA expression; rs5174