Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis.
Identifieur interne : 001536 ( PubMed/Curation ); précédent : 001535; suivant : 001537Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis.
Auteurs : Ming Li [République populaire de Chine] ; Liang Huang [République populaire de Chine] ; Maria Grigoroiu-Serbanescu [Roumanie] ; Sarah E. Bergen [Suède] ; Mikael Landén [Suède] ; Christina M. Hultman [Suède] ; Andreas J. Forstner [Allemagne] ; Jana Strohmaier [Allemagne] ; Julian Hecker [Allemagne] ; Thomas G. Schulze [Allemagne] ; Bertram Müller-Myhsok [Allemagne] ; Andreas Reif [Allemagne] ; Philip B. Mitchell [Australie] ; Nicholas G. Martin [Australie] ; Sven Cichon [Allemagne] ; Markus M. Nöthen [Allemagne] ; Anna Alkelai [Israël] ; Bernard Lerer [Israël] ; Stéphane Jamain [France] ; Marion Leboyer [France] ; Frank Bellivier [France] ; Bruno Etain [France] ; Jean-Pierre Kahn [France] ; Chantal Henry [France] ; Marcella Rietschel [Allemagne]Source :
- Molecular neurobiology [ 1559-1182 ] ; 2016.
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.
DOI: 10.1007/s12035-015-9559-6
PubMed: 26637325
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Nöthen</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Alkelai, Anna" sort="Alkelai, Anna" uniqKey="Alkelai A" first="Anna" last="Alkelai">Anna Alkelai</name><affiliation wicri:level="1"><nlm:affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem</wicri:regionArea></affiliation></author><author><name sortKey="Lerer, Bernard" sort="Lerer, Bernard" uniqKey="Lerer B" first="Bernard" last="Lerer">Bernard Lerer</name><affiliation wicri:level="1"><nlm:affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem</wicri:regionArea></affiliation></author><author><name sortKey="Jamain, Stephane" sort="Jamain, Stephane" uniqKey="Jamain S" first="Stéphane" last="Jamain">Stéphane Jamain</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Leboyer, Marion" sort="Leboyer, Marion" uniqKey="Leboyer M" first="Marion" last="Leboyer">Marion Leboyer</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Bellivier, Frank" sort="Bellivier, Frank" uniqKey="Bellivier F" first="Frank" last="Bellivier">Frank Bellivier</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Etain, Bruno" sort="Etain, Bruno" uniqKey="Etain B" first="Bruno" last="Etain">Bruno Etain</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Kahn, Jean Pierre" sort="Kahn, Jean Pierre" uniqKey="Kahn J" first="Jean-Pierre" last="Kahn">Jean-Pierre Kahn</name><affiliation wicri:level="1"><nlm:affiliation>Fondation Fondamental, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Fondation Fondamental, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Henry, Chantal" sort="Henry, Chantal" uniqKey="Henry C" first="Chantal" last="Henry">Chantal Henry</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Rietschel, Marcella" sort="Rietschel, Marcella" uniqKey="Rietschel M" first="Marcella" last="Rietschel">Marcella Rietschel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26637325</idno><idno type="pmid">26637325</idno><idno type="doi">10.1007/s12035-015-9559-6</idno><idno type="wicri:Area/PubMed/Corpus">001558</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001558</idno><idno type="wicri:Area/PubMed/Curation">001536</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001536</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis.</title><author><name sortKey="Li, Ming" sort="Li, Ming" uniqKey="Li M" first="Ming" last="Li">Ming Li</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan</wicri:regionArea></affiliation></author><author><name sortKey="Huang, Liang" sort="Huang, Liang" uniqKey="Huang L" first="Liang" last="Huang">Liang Huang</name><affiliation wicri:level="1"><nlm:affiliation>First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi</wicri:regionArea></affiliation></author><author><name sortKey="Grigoroiu Serbanescu, Maria" sort="Grigoroiu Serbanescu, Maria" uniqKey="Grigoroiu Serbanescu M" first="Maria" last="Grigoroiu-Serbanescu">Maria Grigoroiu-Serbanescu</name><affiliation wicri:level="1"><nlm:affiliation>Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania. maria.serbanescu@googlemail.com.</nlm:affiliation><country xml:lang="fr">Roumanie</country><wicri:regionArea>Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest</wicri:regionArea></affiliation></author><author><name sortKey="Bergen, Sarah E" sort="Bergen, Sarah E" uniqKey="Bergen S" first="Sarah E" last="Bergen">Sarah E. Bergen</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Landen, Mikael" sort="Landen, Mikael" uniqKey="Landen M" first="Mikael" last="Landén">Mikael Landén</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Hultman, Christina M" sort="Hultman, Christina M" uniqKey="Hultman C" first="Christina M" last="Hultman">Christina M. Hultman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Forstner, Andreas J" sort="Forstner, Andreas J" uniqKey="Forstner A" first="Andreas J" last="Forstner">Andreas J. Forstner</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Strohmaier, Jana" sort="Strohmaier, Jana" uniqKey="Strohmaier J" first="Jana" last="Strohmaier">Jana Strohmaier</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Hecker, Julian" sort="Hecker, Julian" uniqKey="Hecker J" first="Julian" last="Hecker">Julian Hecker</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Schulze, Thomas G" sort="Schulze, Thomas G" uniqKey="Schulze T" first="Thomas G" last="Schulze">Thomas G. Schulze</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Muller Myhsok, Bertram" sort="Muller Myhsok, Bertram" uniqKey="Muller Myhsok B" first="Bertram" last="Müller-Myhsok">Bertram Müller-Myhsok</name><affiliation wicri:level="1"><nlm:affiliation>Max Planck Institute of Psychiatry, Munich, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Max Planck Institute of Psychiatry, Munich</wicri:regionArea></affiliation></author><author><name sortKey="Reif, Andreas" sort="Reif, Andreas" uniqKey="Reif A" first="Andreas" last="Reif">Andreas Reif</name><affiliation wicri:level="1"><nlm:affiliation>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt</wicri:regionArea></affiliation></author><author><name sortKey="Mitchell, Philip B" sort="Mitchell, Philip B" uniqKey="Mitchell P" first="Philip B" last="Mitchell">Philip B. Mitchell</name><affiliation wicri:level="1"><nlm:affiliation>School of Psychiatry, University of New South Wales, Sydney, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Psychiatry, University of New South Wales, Sydney</wicri:regionArea></affiliation></author><author><name sortKey="Martin, Nicholas G" sort="Martin, Nicholas G" uniqKey="Martin N" first="Nicholas G" last="Martin">Nicholas G. Martin</name><affiliation wicri:level="1"><nlm:affiliation>QIMR Berghofer Medical Research Institute, Brisbane, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>QIMR Berghofer Medical Research Institute, Brisbane</wicri:regionArea></affiliation></author><author><name sortKey="Cichon, Sven" sort="Cichon, Sven" uniqKey="Cichon S" first="Sven" last="Cichon">Sven Cichon</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Nothen, Markus M" sort="Nothen, Markus M" uniqKey="Nothen M" first="Markus M" last="Nöthen">Markus M. Nöthen</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, University of Bonn, Bonn</wicri:regionArea></affiliation></author><author><name sortKey="Alkelai, Anna" sort="Alkelai, Anna" uniqKey="Alkelai A" first="Anna" last="Alkelai">Anna Alkelai</name><affiliation wicri:level="1"><nlm:affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem</wicri:regionArea></affiliation></author><author><name sortKey="Lerer, Bernard" sort="Lerer, Bernard" uniqKey="Lerer B" first="Bernard" last="Lerer">Bernard Lerer</name><affiliation wicri:level="1"><nlm:affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</nlm:affiliation><country xml:lang="fr">Israël</country><wicri:regionArea>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem</wicri:regionArea></affiliation></author><author><name sortKey="Jamain, Stephane" sort="Jamain, Stephane" uniqKey="Jamain S" first="Stéphane" last="Jamain">Stéphane Jamain</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Leboyer, Marion" sort="Leboyer, Marion" uniqKey="Leboyer M" first="Marion" last="Leboyer">Marion Leboyer</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Bellivier, Frank" sort="Bellivier, Frank" uniqKey="Bellivier F" first="Frank" last="Bellivier">Frank Bellivier</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Etain, Bruno" sort="Etain, Bruno" uniqKey="Etain B" first="Bruno" last="Etain">Bruno Etain</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Kahn, Jean Pierre" sort="Kahn, Jean Pierre" uniqKey="Kahn J" first="Jean-Pierre" last="Kahn">Jean-Pierre Kahn</name><affiliation wicri:level="1"><nlm:affiliation>Fondation Fondamental, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Fondation Fondamental, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Henry, Chantal" sort="Henry, Chantal" uniqKey="Henry C" first="Chantal" last="Henry">Chantal Henry</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil</wicri:regionArea></affiliation></author><author><name sortKey="Rietschel, Marcella" sort="Rietschel, Marcella" uniqKey="Rietschel M" first="Marcella" last="Rietschel">Marcella Rietschel</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecular neurobiology</title><idno type="eISSN">1559-1182</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="In-Process" Owner="NLM"><PMID Version="1">26637325</PMID><DateCreated><Year>2015</Year><Month>12</Month><Day>05</Day></DateCreated><DateRevised><Year>2017</Year><Month>11</Month><Day>08</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1559-1182</ISSN><JournalIssue CitedMedium="Internet"><Volume>53</Volume><Issue>10</Issue><PubDate><Year>2016</Year><Month>Dec</Month></PubDate></JournalIssue><Title>Molecular neurobiology</Title><ISOAbbreviation>Mol. Neurobiol.</ISOAbbreviation></Journal><ArticleTitle>Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis.</ArticleTitle><Pagination><MedlinePgn>6608-6619</MedlinePgn></Pagination><Abstract><AbstractText>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.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Ming</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Huang</LastName><ForeName>Liang</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Grigoroiu-Serbanescu</LastName><ForeName>Maria</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania. maria.serbanescu@googlemail.com.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bergen</LastName><ForeName>Sarah E</ForeName><Initials>SE</Initials><AffiliationInfo><Affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Landén</LastName><ForeName>Mikael</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hultman</LastName><ForeName>Christina M</ForeName><Initials>CM</Initials><AffiliationInfo><Affiliation>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Forstner</LastName><ForeName>Andreas J</ForeName><Initials>AJ</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Strohmaier</LastName><ForeName>Jana</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hecker</LastName><ForeName>Julian</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Schulze</LastName><ForeName>Thomas G</ForeName><Initials>TG</Initials><AffiliationInfo><Affiliation>Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Müller-Myhsok</LastName><ForeName>Bertram</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Max Planck Institute of Psychiatry, Munich, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Translational Medicine, University of Liverpool, Liverpool, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Reif</LastName><ForeName>Andreas</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Mitchell</LastName><ForeName>Philip B</ForeName><Initials>PB</Initials><AffiliationInfo><Affiliation>School of Psychiatry, University of New South Wales, Sydney, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Black Dog Institute, Sydney, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Martin</LastName><ForeName>Nicholas G</ForeName><Initials>NG</Initials><AffiliationInfo><Affiliation>QIMR Berghofer Medical Research Institute, Brisbane, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cichon</LastName><ForeName>Sven</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, D-52425, Jülich, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nöthen</LastName><ForeName>Markus M</ForeName><Initials>MM</Initials><AffiliationInfo><Affiliation>Institute of Human Genetics, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alkelai</LastName><ForeName>Anna</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lerer</LastName><ForeName>Bernard</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jamain</LastName><ForeName>Stéphane</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Université Paris Est, Faculté de Médecine, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leboyer</LastName><ForeName>Marion</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Université Paris Est, Faculté de Médecine, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bellivier</LastName><ForeName>Frank</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Groupe hospitalier Lariboisière - F. Widal, Pôle de Psychiatrie, Paris, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Université Paris Diderot, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Etain</LastName><ForeName>Bruno</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Université Paris Est, Faculté de Médecine, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kahn</LastName><ForeName>Jean-Pierre</ForeName><Initials>JP</Initials><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d'Arc, Toul, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Henry</LastName><ForeName>Chantal</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Université Paris Est, Faculté de Médecine, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Fondation Fondamental, Créteil, France.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rietschel</LastName><ForeName>Marcella</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Genetic Epidemiology in 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MajorTopicYN="N">rs5174</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>08</Month><Day>26</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2015</Year><Month>11</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2015</Year><Month>12</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2015</Year><Month>12</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>12</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">26637325</ArticleId><ArticleId IdType="doi">10.1007/s12035-015-9559-6</ArticleId><ArticleId IdType="pii">10.1007/s12035-015-9559-6</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix 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