Anna C. Need 1 , Dongliang Ge 1 , Michael E. Weale 2 , Jessica Maia 1 , Sheng Feng 3 , Erin L. Heinzen 1 , Kevin V. Shianna 1 , Woohyun Yoon 1 , Dalia Kasperavičiūtė 4 , Massimo Gennarelli 5 , 6 , Warren J. Strittmatter 7 , Cristian Bonvicini 5 , Giuseppe Rossi 8 , Karu Jayathilake 9 , Philip A. Cola 10 , Joseph P. McEvoy 11 , Richard S. E. Keefe 11 , Elizabeth M. C. Fisher 4 , Pamela L. St. Jean 12 , Ina Giegling 13 , Annette M. Hartmann 13 , Hans-Jürgen Möller 14 , Andreas Ruppert 15 , Gillian Fraser 16 , Caroline Crombie 16 , Lefkos T. Middleton 17 , David St. Clair 16 , Allen D. Roses 18 , Pierandrea Muglia 19 , Clyde Francks 19 , Dan Rujescu 13 , Herbert Y. Meltzer 9 , David B. Goldstein 1 , *
6 February 2009
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.
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.