hide
Free keywords:
LRP8, rs5174, Schizophrenia, Bipolar disorder, mRNA expression
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 x 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 x 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.
