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Mol Neurobiol. 2016 Dec;53(10):6608-6619. Epub 2015 Dec 4.

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

Author information

1
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. limingkiz@gmail.com.
2
First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
3
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania. maria.serbanescu@googlemail.com.
4
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
5
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
6
Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
7
Institute of Human Genetics, University of Bonn, Bonn, Germany.
8
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
9
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
10
Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
11
Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
12
Max Planck Institute of Psychiatry, Munich, Germany.
13
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
14
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
15
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
16
School of Psychiatry, University of New South Wales, Sydney, Australia.
17
Black Dog Institute, Sydney, Australia.
18
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
19
Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.
20
Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, D-52425, Jülich, Germany.
21
Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
22
Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.
23
Université Paris Est, Faculté de Médecine, Créteil, France.
24
Fondation Fondamental, Créteil, France.
25
AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
26
AP-HP, Groupe hospitalier Lariboisière - F. Widal, Pôle de Psychiatrie, Paris, France.
27
Université Paris Diderot, Paris, France.
28
Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d'Arc, Toul, France.

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:

Bipolar disorder; LRP8; Schizophrenia; mRNA expression; rs5174

PMID:
26637325
DOI:
10.1007/s12035-015-9559-6
[Indexed for MEDLINE]

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