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

Mol Neurobiol. 2016 Dec;53(10):6608-6619. doi: 10.1007/s12035-015-9559-6. Epub 2015 Dec 4.


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: Bipolar disorder; LRP8; Schizophrenia; mRNA expression; rs5174.

MeSH terms

  • Bipolar Disorder / genetics
  • Brain / pathology
  • Chromosomes, Human / genetics
  • Fetus / pathology
  • Gene Expression Profiling
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • LDL-Receptor Related Proteins / genetics*
  • LDL-Receptor Related Proteins / metabolism
  • Linkage Disequilibrium / genetics
  • Odds Ratio
  • Polymorphism, Single Nucleotide / genetics
  • Protein Interaction Maps / genetics
  • Psychotic Disorders / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reelin Protein
  • Risk Factors
  • Schizophrenia / genetics
  • Time Factors


  • LDL-Receptor Related Proteins
  • RNA, Messenger
  • Reelin Protein
  • low density lipoprotein receptor-related protein 8
  • RELN protein, human