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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

Hamshere, Marian Lindsay, Walters, James Tynan Rhys, Smith, Rhodri, Richards, Alexander, Green, Elaine Karen, Grozeva, Detelina Valentinova, Jones, Ian Richard, Forty, Elizabeth, Jones, L., Gordon-Smith, Katherine, Riley, B., O'Neill, T., Kendler, K. S., Sklar, P., Purcell, S, Kranz, J., Morris, D., Gill, M., Holmans, Peter Alan, Craddock, Nicholas John, Corvin, A., Owen, Michael John and O'Donovan, Michael Conlon 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 18 (6) , pp. 708-712. 10.1038/mp.2012.67

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Systems Immunity Research Institute (SIURI)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: association; CACNA1C; ITIH3/4; psychosis; SDCCAG8
Additional Information: Corrigendum at http://www.nature.com/mp/journal/v18/n6/full/mp201289a.html. "Following the online publication of this article, the authors noted an error in Dr O’Neill's name. The complete and correct author name is FA O’Neill."
Publisher: Nature Publishing Group
ISSN: 1359-4184
Last Modified: 10 May 2019 20:33
URI: http://orca.cf.ac.uk/id/eprint/37556

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