Need, Anna C.; Ge, Dongliang; Weale, Michael E.; Maia, Jessica; Feng, Sheng; Heinzen, Erin L.; Shianna, Kevin V.; Yoon, Woohyun; Kasperaviciute, Dalia; Gennarelli, Massimo; Strittmatter, Warren J.; Bonvicini, Cristian; Rossi, Giuseppe; Jayathilake, Karu; Cola, Philip A.; McEvoy, Joseph P.; Keefe, Richard S. E.; Fisher, Elizabeth M. C.; St. Jean, Pamela L.; Giegling, Ina; Hartmann, Annette M.; Moeller, Hans-Juergen; Ruppert, Andreas; Fraser, Gillian; Crombie, Caroline; Middleton, Lefkos T.; St. Clair, David; Roses, Allen D.; Muglia, Pierandrea; Francks, Clyde; Rujescu, Dan; Meltzer, Herbert Y.; Goldstein, David B. (Februar 2009): A Genome-Wide Investigation of SNPs and CNVs in Schizophrenia.
In: PLOS Genetics 5(2), e1000373




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.