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Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC
Open accessAbstract
The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
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Cites
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442
Self-citationCommon polygenic variation contributes to risk of schizophrenia and bipolar disorder
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Self-citationCommon variants conferring risk of schizophrenia
†Genetic Risk and Outcome in Psychosis (GROUP), Stefansson, H., Ophoff, R. A., Steinberg, S., Andreassen, O. A., Cichon, S., Rujescu, D., Werge, T., Pietiläinen, O. P. H., Mors, O., et al. (2009) · Nature · doi:10.1038/nature08186 · Cited by 1,677
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Self-citationIdentification of loci associated with schizophrenia by genome-wide association and follow-up
Molecular Genetics of Schizophrenia Collaboration, O'Donovan, M. C., Craddock, N., Norton, N., Williams, H., Peirce, T., Moskvina, V., Nikolov, I., Hamshere, M., Carroll, L., et al. (2008) · Nature Genetics · doi:10.1038/ng.201 · Cited by 1,070
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Biological insights from 108 schizophrenia-associated genetic loci
Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) · Nature · doi:10.1038/nature13595 · Cited by 7,577
GERAD1 Consortium, Pardiñas, A. F., CRESTAR Consortium, Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., Legge, S. E., Bishop, S., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0059-2 · Cited by 1,552
Self-citationGenome-wide association analysis identifies 13 new risk loci for schizophrenia
Multicenter Genetic Studies of Schizophrenia Consortium, Ripke, S., Psychosis Endophenotypes International Consortium, Wellcome Trust Case Control Consortium 2, O'Dushlaine, C., Chambert, K., Moran, J. L., Kähler, A. K., Akterin, S., Bergen, S. E., et al. (2013) · Nature Genetics · doi:10.1038/ng.2742 · Cited by 1,496
Self-citationGenetic variability in the regulation of gene expression in ten regions of the human brain
UK Brain Expression Consortium, Ramasamy, A., North American Brain Expression Consortium, Trabzuni, D., Guelfi, S., Varghese, V., Smith, C., Walker, R., De, T., Coin, L., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3801 · Cited by 644
Analysis of copy number variations at 15 schizophrenia-associated loci
Rees, E., Walters, J. T. R., Georgieva, L., Isles, A. R., Chambert, K. D., Richards, A. L., Mahoney-Davies, G., Legge, S. E., Moran, J. L., McCarroll, S. A., et al. (2014) · British Journal of Psychiatry · doi:10.1192/bjp.bp.113.131052 · Cited by 443
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Metadata
- Authors
- Hamshere, M. L., Walters, J. T. R., Smith, R., Richards, A. L., Green, E., Grozeva, D., Jones, I., Forty, L., Jones, L., Gordon-Smith, K., Riley, B., O'Neill, T., Kendler, K. S., Sklar, P., Purcell, S., Kranz, J., The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), W. T. C. C. C. (., Morris, D., Gill, M., Holmans, P., Craddock, N., Corvin, A., Owen, M. J., & O'Donovan, M. C.
- Venue
- Molecular Psychiatry
- Published
- 2012-05-22
- Volume
- 18
- Issue
- 6
- Pages
- 708-712
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2149101657
- Cited by
- 246
- References
- 8
- FWCI
- 19.47
- Type
- journal article
- Language
- en
- Open access
- green
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- Hamshere, M. L., Walters, J. T. R., Smith, R., Richards, A. L., Green, E., Grozeva, D., Jones, I., Forty, L., Jones, L., Gordon-Smith, K., Riley, B., O'Neill, T., Kendler, K. S., Sklar, P., Purcell, S., Kranz, J., The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), W. T. C. C. C. (., Morris, D., Gill, M., . . . O'Donovan, M. C. (2013). Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Molecular Psychiatry. https://doi.org/10.1038/mp.2012.67
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