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Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

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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 (P meta = 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.

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Acknowledgments

We are grateful to all the voluntary donors of DNA samples in this study. We thank members of Psychiatric Genomics Consortium, who shared the PGC GWAS data. This work was supported by the German Federal Ministry of Education and Research (BMBF) through the Integrated Genome Research Network (IG) MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia; grant 01GS08144 to SC and MMN, grant 01GS08147 to MR), under the auspices of the National Genome Research Network plus (NGFNplus), and through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e: Med Programme (grant 01ZX1314A to SC and MMN, grant 01ZX1314G to MR). MMN is a member of the DFG-funded Excellence-Cluster ImmunoSensation. The Romanian sample recruitment and genotyping was funded by UEFISCDI, Bucharest, Romania, grant no. 89/2012 to M.G.S. and by the German Federal Ministry of Education and Research (BMBF), MooDS Project, grant no. 01GS08144 to M.M.N. Funding for the Swedish collection was provided by the Stanley Center for Psychiatric Research, Broad Institute from a grant from Stanley Medical Research Institute. We also wish to thank the BBMRI.se and KI Biobank at Karolinska Institutet for professional biobank service.

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    Authors and Affiliations

    1. 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

      Ming Li

    2. First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China

      Liang Huang

    3. Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania

      Maria Grigoroiu-Serbanescu

    4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

      Sarah E. Bergen, Mikael Landén & Christina M. Hultman

    5. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA

      Sarah E. Bergen

    6. Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden

      Mikael Landén

    7. Institute of Human Genetics, University of Bonn, Bonn, Germany

      Andreas J. Forstner, Julian Hecker, Sven Cichon & Markus M. Nöthen

    8. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

      Andreas J. Forstner, Sven Cichon & Markus M. Nöthen

    9. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

      Jana Strohmaier & Marcella Rietschel

    10. Institute of Genomic Mathematics, University of Bonn, Bonn, Germany

      Julian Hecker

    11. Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany

      Thomas G. Schulze

    12. Max Planck Institute of Psychiatry, Munich, Germany

      Bertram Müller-Myhsok

    13. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

      Bertram Müller-Myhsok

    14. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

      Bertram Müller-Myhsok

    15. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany

      Andreas Reif

    16. School of Psychiatry, University of New South Wales, Sydney, Australia

      Philip B. Mitchell

    17. Black Dog Institute, Sydney, Australia

      Philip B. Mitchell

    18. QIMR Berghofer Medical Research Institute, Brisbane, Australia

      Nicholas G. Martin

    19. Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland

      Sven Cichon

    20. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, D-52425, Jülich, Germany

      Sven Cichon

    21. Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel

      Anna Alkelai & Bernard Lerer

    22. Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France

      Stéphane Jamain, Marion Leboyer, Frank Bellivier, Bruno Etain & Chantal Henry

    23. Université Paris Est, Faculté de Médecine, Créteil, France

      Stéphane Jamain, Marion Leboyer, Bruno Etain & Chantal Henry

    24. Fondation Fondamental, Créteil, France

      Stéphane Jamain, Marion Leboyer, Frank Bellivier, Bruno Etain, Jean-Pierre Kahn & Chantal Henry

    25. AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France

      Marion Leboyer, Frank Bellivier, Bruno Etain & Chantal Henry

    26. AP-HP, Groupe hospitalier Lariboisière - F. Widal, Pôle de Psychiatrie, Paris, France

      Frank Bellivier

    27. Université Paris Diderot, Paris, France

      Frank Bellivier

    28. Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d’Arc, Toul, France

      Jean-Pierre Kahn

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    1. Ming Li
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    Consortia

    MooDS Consortium

    The Swedish Bipolar Study Group

    Corresponding authors

    Correspondence to Ming Li or Maria Grigoroiu-Serbanescu.

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    The authors declare that they have no competing interests.

    Additional information

    Additional Members from the Bipolar Disorder Group of the MooDS Consortium

    Thomas W. Mühleisen,1,2,3 Markus Leber,4 Thomas G. Schulze,5 Franziska Degenhardt,1,2 Jens Treutlein,6 Manuel Mattheisen,7,8 Andrea Hofmann,1,2 René Breuer,6 Sandra Meier,6,9 Stefan Herms,1,2,10 Per Hoffmann,1,2,3,10 André Lacour,11 Stephanie H. Witt,6 Fabian Streit,6 Susanne Lucae,12 Wolfgang Maier,13 Markus Schwarz,14 Helmut Vedder,14 Jutta Kammerer-Ciernioch,14 Andrea Pfennig,15 Michael Bauer,15 Martin Hautzinger,16 Adam Wright,17,18 Janice M. Fullerton,19,20 Peter R. Schofield,19,20 Grant W. Montgomery,21 Sarah E. Medland,21 Scott D. Gordon,21 Tim Becker,4,11 Johannes Schumacher,1,2 Peter Propping. 1

    1Institute of Human Genetics, University of Bonn, Germany

    2Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    3Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Germany

    4Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Germany

    5Institute of Psychiatric Phenomics and Genomics, Ludwig Maximilian University Munich, Munich, Germany

    6Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Germany

    7Department of Biomedicine, Aarhus University, Denmark

    8Institute for Genomics Mathematics, University of Bonn, Germany

    9National Centre Register-Based Research, Aarhus University, Denmark

    10Division of Medical Genetics and Department of Biomedicine, University of Basel, Switzerland

    11German Center for Neurodegenerative Diseases DZNE, Bonn, Germany

    12Max Planck Institute of Psychiatry, Munich, Germany

    13Department of Psychiatry, University of Bonn, Germany

    14Psychiatric Center Nordbaden, Wiesloch, Germany

    15Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Dresden, Germany

    16Department of Psychology, Clinical Psychology and Psychotherapy, Eberhard Karls University Tübingen, Germany

    17School of Psychiatry, University of New South Wales Randwick, Australia

    18Black Dog Institute, Prince of Wales Hospital Randwick, Australia

    19Neuroscience Research Australia, Sydney, Australia

    20School of Medical Sciences Faculty of Medicine, University of New South Wales Sydney, Australia

    21Queensland Institute of Medical Research QIMR, Brisbane, Australia

    Members of the Swedish Bipolar Study Group

    Lena Backlund,1 Louise Frisén,1 Catharina Lavebratt,2 Martin Schalling,2 Urban Ösby.1

    1Department of Clinical Neuroscience Neurogenetics Unit, Stockholm, Sweden

    2Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    Ming Li and Liang Huang contributed equally to this work.

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    Li, M., Huang, L., Grigoroiu-Serbanescu, M. et al. Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis. Mol Neurobiol 53, 6608–6619 (2016). https://doi.org/10.1007/s12035-015-9559-6

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