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Molecular Neurobiology

, Volume 53, Issue 10, pp 6608–6619 | Cite as

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

  • Ming LiEmail author
  • Liang Huang
  • Maria Grigoroiu-SerbanescuEmail author
  • Sarah E. Bergen
  • Mikael Landén
  • Christina M. Hultman
  • Andreas J. Forstner
  • Jana Strohmaier
  • Julian Hecker
  • Thomas G. Schulze
  • Bertram Müller-Myhsok
  • Andreas Reif
  • Philip B. Mitchell
  • Nicholas G. Martin
  • Sven Cichon
  • Markus M. Nöthen
  • Anna Alkelai
  • Bernard Lerer
  • Stéphane Jamain
  • Marion Leboyer
  • Frank Bellivier
  • Bruno Etain
  • Jean-Pierre Kahn
  • Chantal Henry
  • Marcella Rietschel
  • MooDS Consortium
  • The Swedish Bipolar Study Group
Article

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.

Keywords

LRP8 rs5174 Schizophrenia Bipolar disorder mRNA expression 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12035_2015_9559_MOESM1_ESM.pdf (578 kb)
ESM 1 (PDF 577 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Ming Li
    • 1
    Email author
  • Liang Huang
    • 2
  • Maria Grigoroiu-Serbanescu
    • 3
    Email author
  • Sarah E. Bergen
    • 4
    • 5
  • Mikael Landén
    • 4
    • 6
  • Christina M. Hultman
    • 4
  • Andreas J. Forstner
    • 7
    • 8
  • Jana Strohmaier
    • 9
  • Julian Hecker
    • 7
    • 10
  • Thomas G. Schulze
    • 11
  • Bertram Müller-Myhsok
    • 12
    • 13
    • 14
  • Andreas Reif
    • 15
  • Philip B. Mitchell
    • 16
    • 17
  • Nicholas G. Martin
    • 18
  • Sven Cichon
    • 7
    • 8
    • 19
    • 20
  • Markus M. Nöthen
    • 7
    • 8
  • Anna Alkelai
    • 21
  • Bernard Lerer
    • 21
  • Stéphane Jamain
    • 22
    • 23
    • 24
  • Marion Leboyer
    • 22
    • 23
    • 24
    • 25
  • Frank Bellivier
    • 22
    • 24
    • 25
    • 26
    • 27
  • Bruno Etain
    • 22
    • 23
    • 24
    • 25
  • Jean-Pierre Kahn
    • 24
    • 28
  • Chantal Henry
    • 22
    • 23
    • 24
    • 25
  • Marcella Rietschel
    • 9
  • MooDS Consortium
  • The Swedish Bipolar Study Group
  1. 1.Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan ProvinceKunming Institute of ZoologyKunmingChina
  2. 2.First Affiliated Hospital of Gannan Medical UniversityGanzhouChina
  3. 3.Biometric Psychiatric Genetics Research UnitAlexandru Obregia Clinical Psychiatric HospitalBucharestRomania
  4. 4.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  5. 5.Stanley Center for Psychiatric ResearchBroad Institute of Harvard and MITCambridgeUSA
  6. 6.Section of Psychiatry and NeurochemistrySahlgrenska Academy at Gothenburg UniversityGothenburgSweden
  7. 7.Institute of Human GeneticsUniversity of BonnBonnGermany
  8. 8.Department of Genomics, Life and Brain CenterUniversity of BonnBonnGermany
  9. 9.Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty MannheimUniversity of HeidelbergHeidelbergGermany
  10. 10.Institute of Genomic MathematicsUniversity of BonnBonnGermany
  11. 11.Institute of Psychiatric Phenomics and GenomicsLudwig-Maximilians-University MunichMunichGermany
  12. 12.Max Planck Institute of PsychiatryMunichGermany
  13. 13.Munich Cluster for Systems Neurology (SyNergy)MunichGermany
  14. 14.Institute of Translational MedicineUniversity of LiverpoolLiverpoolUK
  15. 15.Department of Psychiatry, Psychosomatic Medicine and PsychotherapyUniversity Hospital FrankfurtFrankfurtGermany
  16. 16.School of PsychiatryUniversity of New South WalesSydneyAustralia
  17. 17.Black Dog InstituteSydneyAustralia
  18. 18.QIMR Berghofer Medical Research InstituteBrisbaneAustralia
  19. 19.Division of Medical Genetics, University Hospital Basel and Department of BiomedicineUniversity of BaselBaselSwitzerland
  20. 20.Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic ImagingResearch Centre JülichJülichGermany
  21. 21.Biological Psychiatry Laboratory, Department of PsychiatryHadassah - Hebrew University Medical CenterJerusalemIsrael
  22. 22.Inserm U 955, IMRB, Psychiatrie TranslationnelleCréteilFrance
  23. 23.Université Paris Est, Faculté de MédecineCréteilFrance
  24. 24.Fondation FondamentalCréteilFrance
  25. 25.AP-HP, Hôpitaux Universitaires Henri Mondor, DHU PepsyPôle de PsychiatrieCréteilFrance
  26. 26.AP-HP, Groupe hospitalier Lariboisière - F. WidalPôle de PsychiatrieParisFrance
  27. 27.Université Paris DiderotParisFrance
  28. 28.Département de Psychiatrie et de Psychologie CliniqueCHU de Nancy, Hôpital Jeanne d’ArcToulFrance

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