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  A genome-wide investigation of SNPs and CNVs in schizophrenia

Need, A. C., Ge, D., Weale, M. E., Maia, J., Feng, S., Heinzen, E. L., et al. (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics, 5(2), e1000373. doi:10.1371/journal.pgen.1000373.

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Need, Anna C.1, Autor
Ge, Dongliang1, Autor
Weale, Michael E.2, Autor
Maia, Jessica1, Autor
Feng, Sheng3, Autor
Heinzen, Erin L.1, Autor
Shianna, Kevin V.1, Autor
Yoon, Woohyun1, Autor
Kasperavičiūtė, Dalia4, Autor
Gennarelli, Massimo5, 6, Autor
Strittmatter, Warren J.7, Autor
Bonvicini, Cristian5, Autor
Rossi, Giuseppe8, Autor
Jayathilake, Karu9, Autor
Cola, Philip A.10, Autor
McEvoy, Joseph P.11, Autor
Keefe, Richard S. E.11, Autor
Fisher, Elizabeth M. C.4, Autor
St. Jean, Pamela L.12, Autor
Giegling, Ina13, Autor
Hartmann, Annette M.13, AutorMöller, Hans-Jürgen14, AutorRuppert, Andreas15, AutorFraser, Gillian16, AutorCrombie, Caroline16, AutorMiddleton, Lefkos T.17, AutorSt. Clair, David16, AutorRoses, Allen D.18, AutorMuglia, Pierandrea19, AutorFrancks, Clyde19, Autor           Rujescu, Dan13, AutorMeltzer, Herbert Y.9, AutorGoldstein, David B.1, Autor mehr..
Affiliations:
1 Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America, ou_persistent22              
2 Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom, ou_persistent22              
3 Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina, United States of America, ou_persistent22              
4 Institute of Neurology, University College London, London, United Kingdom, ou_persistent22              
5 Genetic Unit, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy, ou_persistent22              
6 Department of Biomedical Science and Biotech, University of Brescia, Brescia, Italy, ou_persistent22              
7 Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America, ou_persistent22              
8 Psychiatric Unit, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy, ou_persistent22              
9 Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America, ou_persistent22              
10University Hospitals Case Medical Center, Cleveland, Ohio, United States of America, ou_persistent22              
11Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, United States of America, ou_persistent22              
12Genetics Division, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America, ou_persistent22              
13Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany, ou_persistent22              
14Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany, ou_persistent22              
15Genetics Research Centre GmbH (GRC), Munich, Germany, ou_persistent22              
16Department of Mental Health, University of Aberdeen, Aberdeen, United Kingdom, ou_persistent22              
17Division of Neuroscience and Mental Health, Neuroscience Laboratories, Burlington Danes, Hammersmith Hospital, London, United Kingdom, ou_persistent22              
18Deane Drug Discovery Institute, Duke University Medical Center, Durham, North Carolina, United States of America, ou_persistent22              
19Medical Genetics, GlaxoSmithKline R&D, Verona, Italy, ou_persistent22              

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 Zusammenfassung: We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
 Zusammenfassung: Schizophrenia is a highly heritable disease. While the drugs commonly used to treat schizophrenia offer important relief from some symptoms, other symptoms are not well treated, and the drugs cause serious adverse effects in many individuals. This has fueled intense interest over the years in identifying genetic contributors to schizophrenia. In this paper, we first show that common genetic variants, the focus of most research until recently, do not seem to have a major impact on schizophrenia predisposition. We then provide further evidence that very rare, large DNA deletions and duplications contribute to or explain a minority of schizophrenia cases. Although the small number of events identified here do not restrict focus to a finite set of molecular pathways, we do show one event that deletes a gene known to interact with DISC1, a gene known to cause psychiatric problems in one family. Such convergent findings have potential implications for the development of new therapies and patient subclassifications. We conclude that schizophrenia genetics research must turn sharply toward the identification of rare genetic contributors and that the most important tool in this effort will be complete whole-genome sequencing of patients whose clinical characteristics have been very thoroughly assessed.

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 Datum: 2009-02-062009-02
 Publikationsstatus: Erschienen
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 Art der Begutachtung: Expertenbegutachtung
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Titel: PLoS Genetics
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: San Francisco, USA : Public Library of Science
Seiten: - Band / Heft: 5 (2) Artikelnummer: - Start- / Endseite: e1000373 Identifikator: Anderer: PLoS Genet
Anderer: plos
Anderer: plosgen
ISSN: 1553-7390
ISSN: 1553-7404