GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia

Genetic Risk and Outcome in Psychosis (GROUP), The International Schizophrenia Consortium (ISC), Gillian Fraser

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r2=0.008; rs10043986-rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10-4and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10-4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

Original languageEnglish
Pages (from-to)1117-1129
Number of pages13
JournalMolecular Psychiatry
Volume16
Issue number11
DOIs
Publication statusPublished - 1 Nov 2011

Fingerprint

Data Mining
Genome-Wide Association Study
Cardiomyopathies
Schizophrenia
Odds Ratio
Confidence Intervals
Antipsychotic Agents
Genes
Clinical Trials
Biological Phenomena
Information Services
Linkage Disequilibrium
Computational Biology
Haplotypes
Single Nucleotide Polymorphism
Meta-Analysis
Molecular Biology
Datasets

Keywords

  • association study
  • cardiomyopathy
  • GWA data mining
  • meta-analysis
  • schizophrenia

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Genetic Risk and Outcome in Psychosis (GROUP), The International Schizophrenia Consortium (ISC), & Fraser, G. (2011). GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. Molecular Psychiatry, 16(11), 1117-1129. https://doi.org/10.1038/mp.2010.96

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. / Genetic Risk and Outcome in Psychosis (GROUP); The International Schizophrenia Consortium (ISC); Fraser, Gillian.

In: Molecular Psychiatry, Vol. 16, No. 11, 01.11.2011, p. 1117-1129.

Research output: Contribution to journalArticle

Genetic Risk and Outcome in Psychosis (GROUP), The International Schizophrenia Consortium (ISC) & Fraser, G 2011, 'GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia' Molecular Psychiatry, vol. 16, no. 11, pp. 1117-1129. https://doi.org/10.1038/mp.2010.96
Genetic Risk and Outcome in Psychosis (GROUP), The International Schizophrenia Consortium (ISC), Fraser G. GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. Molecular Psychiatry. 2011 Nov 1;16(11):1117-1129. https://doi.org/10.1038/mp.2010.96
Genetic Risk and Outcome in Psychosis (GROUP) ; The International Schizophrenia Consortium (ISC) ; Fraser, Gillian. / GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. In: Molecular Psychiatry. 2011 ; Vol. 16, No. 11. pp. 1117-1129.
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abstract = "We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r2=0.008; rs10043986-rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95{\%} confidence interval (CI)=1.04-1.18, P=8.2 × 10-4and rs4704591, OR=1.07, 95{\%} CI=1.03-1.11, P=3.0 × 10-4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95{\%} CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95{\%} CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.",
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note = "We thank the volunteers, patients and their family members for participating in this study. This study was supported in part by a research grant (07R-1770) from the Stanley Medical Research Institute and an Independent Investigator Award from NARSAD to XC, and by grants to investigators involved in the collection and analyses of the samples from CATIE, GAIN, the international schizophrenia consortium and other independent samples (National Institutes of Health (MH41953, MH63480, MH56242, MH078075); NARSAD Young Investigator Award; Donald & Barbara Zucker Foundation, USA; the Medical Research Council and the Wellcome Trust Foundation, UK; the Research Council of Norway (Grant No. 163070/V50, 167153/V50); the South-Eastern Norway Health Authority (123/2004); Science Foundation Ireland and Health Research Board, Ireland; the Lundbeck Foundation and Danish National Advanced Technology Foundation, Denmark). The Ashkenazi samples are part of the Hebrew University Genetic Resource (HUGR). The principal investigators of the CATIE trial were Jeffrey A Lieberman, T Scott Stroup and Joseph P McEvoy. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. The principle investigators for the MGS were Pablo Gejman and Douglas Levinson. MGS study was supported by funding from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. Genotyping of part of the sample was supported by GAIN and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources.",
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T1 - GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia

AU - Genetic Risk and Outcome in Psychosis (GROUP)

AU - The International Schizophrenia Consortium (ISC)

AU - Chen, X.

AU - Lee, G.

AU - Maher, B. S.

AU - Fanous, A. H.

AU - Chen, J.

AU - Zhao, Z.

AU - Guo, A.

AU - Van Den Oord, E.

AU - Sullivan, P. F.

AU - Shi, J.

AU - Levinson, D. F.

AU - Gejman, P. V.

AU - Sanders, A.

AU - Duan, J.

AU - Owen, M. J.

AU - Craddock, N. J.

AU - O'Donovan, Michael C.

AU - Blackman, J.

AU - Lewis, D.

AU - Kirov, G. K.

AU - Qin, W.

AU - Schwab, S.

AU - Wildenauer, D.

AU - Chowdari, K.

AU - Nimgaonkar, V.

AU - Straub, R. E.

AU - Weinberger, D. R.

AU - O'Neill, F. A.

AU - Walsh, D.

AU - Bronstein, M.

AU - Darvasi, A.

AU - Lencz, T.

AU - Malhotra, A. K.

AU - Rujescu, D.

AU - Giegling, I.

AU - Werge, T.

AU - Hansen, T.

AU - Ingason, A.

AU - Nöethen, M. M.

AU - Rietschel, M.

AU - Cichon, S.

AU - Djurovic, S.

AU - Andreassen, O. A.

AU - Cantor, R. M.

AU - Ophoff, R.

AU - Corvin, A.

AU - St Clair, D.

AU - Crombie, Caroline

AU - Fraser, Gillian

AU - Kuan, Soh Leh

AU - St Clair, D.

N1 - We thank the volunteers, patients and their family members for participating in this study. This study was supported in part by a research grant (07R-1770) from the Stanley Medical Research Institute and an Independent Investigator Award from NARSAD to XC, and by grants to investigators involved in the collection and analyses of the samples from CATIE, GAIN, the international schizophrenia consortium and other independent samples (National Institutes of Health (MH41953, MH63480, MH56242, MH078075); NARSAD Young Investigator Award; Donald & Barbara Zucker Foundation, USA; the Medical Research Council and the Wellcome Trust Foundation, UK; the Research Council of Norway (Grant No. 163070/V50, 167153/V50); the South-Eastern Norway Health Authority (123/2004); Science Foundation Ireland and Health Research Board, Ireland; the Lundbeck Foundation and Danish National Advanced Technology Foundation, Denmark). The Ashkenazi samples are part of the Hebrew University Genetic Resource (HUGR). The principal investigators of the CATIE trial were Jeffrey A Lieberman, T Scott Stroup and Joseph P McEvoy. The CATIE trial was funded by a grant from the National Institute of Mental Health (N01 MH900001) along with MH074027 (PI PF Sullivan). Genotyping was funded by Eli Lilly and Company. The principle investigators for the MGS were Pablo Gejman and Douglas Levinson. MGS study was supported by funding from the National Institute of Mental Health and the National Alliance for Research on Schizophrenia and Depression. Genotyping of part of the sample was supported by GAIN and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Center for Genotyping and Analysis at the Broad Institute of Harvard and MIT with support from the National Center for Research Resources.

PY - 2011/11/1

Y1 - 2011/11/1

N2 - We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r2=0.008; rs10043986-rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10-4and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10-4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

AB - We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r2=0.008; rs10043986-rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10-4and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10-4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.

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