Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e1000373 |
| Journal | PLoS genetics |
| Volume | 5 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2009 |
Funding
We would like to thank Dr. Hreinn Stefánsson of DeCODE genetics for making available association data for the top ADAMTSL3 SNPs. Dr Kai Wang was extremely helpful in answering questions about the PennCNV software. We thank Drs. David Altshuler and Steve McCarroll for sending us the CNP tagging SNPs. We also thank Dr. James S. Albert for assessing expression patterns in mouse brain, Dr. Suneel Apte for comments on the manuscript and advice, and the IGSP and Duke Medical Center for support for this work. Finally, we thank all co-workers at the Department of Psychiatry, LMU Munich for their excellent contribution to the clinical characterization of the subjects and the laboratory work. Recruitment of the patients from Munich was partially supported by GlaxoSmithKline (GSK). We are grateful to the Genetics Research Centre GmbH, an initiative by GSK and LMU, for genotyping the Munich replication samples. We thank Edward and Helen Hintz, Robert and Lee Peterson, and Robert and Fran Weissman (Ritter Foundation) for support of the US patient component.
ASJC Scopus subject areas
- Ecology, Evolution, Behavior and Systematics
- Molecular Biology
- Genetics
- Genetics(clinical)
- Cancer Research