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; Alan Richards; E Green; D Grozeva; Ian Jones; L Forty; Leigh Robert Jones; K Gordon-Smith; B Riley; T O'Neill; K S Kendler; P Sklar; S Purcell; J Kranz; David Jackson Morris; M Gill; P Holmans; N Craddock; A Corvin; M J Owen; M C O'Donovan; The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), Wellcome Trust Case Control Consortium+ (WTCCC+), Wellcome Trust Case Control Consortium 2 (WTCCC2); Thomas Hansen; Line Olsen; Andrés Ingason; Henriette Schmock; Celina Skjødt; Anders Rosengren; Louise.K.Enggaard Høffding; Johan Hilge Thygesen; Thomas Mears Werge

doi: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

M L Hamshere, J T R Walters, R Smith, Alan Richards, E Green, D Grozeva, Ian Jones, L Forty, Leigh Robert Jones, K Gordon-Smith, B Riley, T O'Neill, K S Kendler, P Sklar, S Purcell, J Kranz, David Jackson Morris, M Gill, P Holmans, N CraddockA Corvin, M J Owen, M C O'Donovan, The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), Wellcome Trust Case Control Consortium+ (WTCCC+), Wellcome Trust Case Control Consortium 2 (WTCCC2), Thomas Hansen, Line Olsen, Andrés Ingason, Henriette Schmock, Celina Skjødt, Anders Rosengren, Louise.K.Enggaard Høffding, Johan Hilge Thygesen, Thomas Mears Werge

164 Citations (Scopus)

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 language	English
Journal	Molecular Psychiatry
ISSN	1359-4184
DOIs	https://doi.org/10.1038/mp.2012.67
Publication status	Published - Jun 2013

Access to Document

10.1038/mp.2012.67

Cite this

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

Hamshere, ML, Walters, JTR, Smith, R, Richards, A, Green, E, Grozeva, D, Jones, I, Forty, L, Jones, LR, Gordon-Smith, K, Riley, B, O'Neill, T, Kendler, KS, Sklar, P, Purcell, S, Kranz, J, Morris, DJ, Gill, M, Holmans, P, Craddock, N, Corvin, A, Owen, MJ, O'Donovan, MC, The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), Wellcome Trust Case Control Consortium+ (WTCCC+), Wellcome Trust Case Control Consortium 2 (WTCCC2), Hansen, T, Olsen, L, Ingason, A, Schmock, H, Skjødt, C, Rosengren, A, Høffding, LKE, Thygesen, JH & Werge, TM 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

@article{ec0614413f634434b5edd999c88592c3,

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

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.",

author = "Hamshere, {M L} and Walters, {J T R} and R Smith and Alan Richards and E Green and D Grozeva and Ian Jones and L Forty and Jones, {Leigh Robert} 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 Morris, {David Jackson} and M Gill and P Holmans and N Craddock and A Corvin and Owen, {M J} and O'Donovan, {M C} and Thomas Werge and Thomas Hansen and Line Olsen and Andr{\'e}s Ingason and Henriette Schmock and Celina Skj{\o}dt and Anders Rosengren and Louise.K.Enggaard H{\o}ffding and Thygesen, {Johan Hilge} and Werge, {Thomas Mears}",

year = "2013",

month = jun,

doi = "10.1038/mp.2012.67",

language = "English",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "nature publishing group",

}

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, Alan

AU - Green, E

AU - Grozeva, D

AU - Jones, Ian

AU - Forty, L

AU - Jones, Leigh Robert

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, David Jackson

AU - Gill, M

AU - Holmans, P

AU - Craddock, N

AU - Corvin, A

AU - Owen, M J

AU - O'Donovan, M C

AU - The Schizophrenia Psychiatric Genome-wide Association Study Consortium (PGC), Wellcome Trust Case Control Consortium+ (WTCCC+), Wellcome Trust Case Control Consortium 2 (WTCCC2)

AU - Hansen, Thomas

AU - Olsen, Line

AU - Ingason, Andrés

AU - Schmock, Henriette

AU - Skjødt, Celina

AU - Rosengren, Anders

AU - Høffding, Louise.K.Enggaard

AU - Thygesen, Johan Hilge

AU - Werge, Thomas Mears

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

U2 - 10.1038/mp.2012.67

DO - 10.1038/mp.2012.67

M3 - Journal article

C2 - 22614287

SN - 1359-4184

JO - Molecular Psychiatry

JF - Molecular Psychiatry

ER -

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

Abstract

Access to Document

Fingerprint

Cite this