Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis
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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.
KeywordsLRP8 rs5174 Schizophrenia Bipolar disorder mRNA expression
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.
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