Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

M. L. Hamshere, J. T.R. Walters, R. Smith, A. L. Richards, E. Green, D. Grozeva, I. Jones, L. Forty, L. Jones, K. Gordon-Smith, B. Riley, T. O'Neill, K. S. Kendler, P. Sklar, S. Purcell, J. Kranz, D. Morris, M. Gill, P. Holmans, N. CraddockA. Corvin, M. J. Owen, M. C. O'Donovan*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)708-712
Number of pages5
JournalMolecular Psychiatry
Volume18
Early online date22 May 2012
DOIs
Publication statusPublished - 2013

Fingerprint

Schizophrenia
Genome
Single Nucleotide Polymorphism
Bipolar Disorder
Major Histocompatibility Complex
Alleles
Clozapine
Genome-Wide Association Study
Psychiatry
Confidence Intervals
Research

Keywords

  • Association
  • CACNA1C
  • ITIH3/4
  • Psychosis
  • SDCCAG8

Cite this

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. ; Morris, D. ; Gill, M. ; Holmans, P. ; Craddock, N. ; Corvin, A. ; Owen, M. J. ; O'Donovan, M. C. / Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. In: Molecular Psychiatry. 2013 ; Vol. 18. pp. 708-712.
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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.",
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author = "Hamshere, {M. L.} and Walters, {J. T.R.} and R. Smith and Richards, {A. L.} and E. Green and D. Grozeva and I. Jones and L. Forty and L. Jones and K. Gordon-Smith and B. Riley and T. O'Neill and Kendler, {K. S.} and P. Sklar and S. Purcell and J. Kranz and D. Morris and M. Gill and P. Holmans and N. Craddock and A. Corvin and Owen, {M. J.} and O'Donovan, {M. C.}",
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Hamshere, ML, Walters, JTR, Smith, R, Richards, AL, Green, E, Grozeva, D, Jones, I, Forty, L, Jones, L, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, KS, Sklar, P, Purcell, S, Kranz, J, Morris, D, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, MJ & O'Donovan, MC 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, vol. 18, pp. 708-712. https://doi.org/10.1038/mp.2012.67

Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. / 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.; Morris, D.; Gill, M.; Holmans, P.; Craddock, N.; Corvin, A.; Owen, M. J.; O'Donovan, M. C.

In: Molecular Psychiatry, Vol. 18, 2013, p. 708-712.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

AU - Hamshere, M. L.

AU - Walters, J. T.R.

AU - Smith, R.

AU - Richards, A. L.

AU - Green, E.

AU - Grozeva, D.

AU - Jones, I.

AU - Forty, L.

AU - Jones, L.

AU - Gordon-Smith, K.

AU - Riley, B.

AU - O'Neill, T.

AU - Kendler, K. S.

AU - Sklar, P.

AU - Purcell, S.

AU - Kranz, J.

AU - Morris, D.

AU - Gill, M.

AU - Holmans, P.

AU - Craddock, N.

AU - Corvin, A.

AU - Owen, M. J.

AU - O'Donovan, M. C.

PY - 2013

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