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

Ming Li, Liang Huang, Maria Grigoroiu-Serbanescu, 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 LeboyerFrank Bellivier, Bruno Etain, Jean Pierre Kahn, Chantal Henry, Marcella Rietschel, Consortium Moods Consortium, Swedish Bipolar Study Group The Swedish Bipolar Study Group

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Dec 4 2015
Externally publishedYes

Keywords

  • Bipolar disorder
  • LRP8
  • mRNA expression
  • rs5174
  • Schizophrenia

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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