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

X. Chen, G. Lee, B. S. Maher, A. H. Fanous, J. Chen, Z. Zhao, A. Guo, E. Van Den Oord, P. F. Sullivan, J. Shi, D. F. Levinson, P. V. Gejman, A. Sanders, J. Duan, M. J. Owen, N. J. Craddock, Michael C. O'Donovan, J. Blackman, D. Lewis, G. K. KirovW. Qin, S. Schwab, D. Wildenauer, K. Chowdari, V. Nimgaonkar, R. E. Straub, D. R. Weinberger, F. A. O'Neill, D. Walsh, M. Bronstein, A. Darvasi, T. Lencz, A. K. Malhotra, D. Rujescu, I. Giegling, T. Werge, T. Hansen, A. Ingason, M. M. Nöethen, M. Rietschel, S. Cichon, S. Djurovic, O. A. Andreassen, R. M. Cantor, R. Ophoff, A. Corvin, D. W. Morris, M. Gill, C. N. Pato, M. T. Pato, A. Macedo, H. M.D. Gurling, A. McQuillin, J. Pimm, C. Hultman, P. Lichtenstein, P. Sklar, S. M. Purcell, E. Scolnick, D. St Clair, D. H.R. Blackwood, K. S. Kendler, René S. Kahn, Don H. Linszen, Jim Van Os, Durk Wiersma, Richard Bruggeman, Wiepke Cahn, Lieuwe De Haan, Lydia Krabbendam, Inez Myin-Germeys, Peter A. Holmans, Nigel M. Williams, Lyudmila Georgieva, Ivan Nikolov, N. Norton, H. Williams, Draga Toncheva, Vihra Milanova, Christina M. Hultman, Emma F. Thelander, Patrick Sullivan, Colm T. O'Dushlaine, Elaine Kenny, Emma M. Quinn, Khalid Choudhury, Susmita Datta, Srinivasa Thirumalai, Vinay Puri, Robert Krasucki, Jacob Lawrence, Digby Quested, Nicholas Bass, Hugh Gurling, Caroline Crombie, Gillian Fraser, Soh Leh Kuan, Nicholas Walker, Walter J. Muir, Kevin A. McGhee, Ben Pickard, Pat Malloy, Alan W. Maclean, Margaret Van Beck, Naomi R. Wray, Stuart Macgregor, Peter M. Visscher, Helena Medeiros, Frank Middleton, Celia Carvalho, Christopher Morley, Ayman Fanous, David Conti, James A. Knowles, Carlos Paz Ferreira, M. Helena Azevedo, Jennifer L. Stone, Douglas M. Ruderfer, Andrew N. Kirby, Manuel A.R. Ferreira, Mark J. Daly, Kimberly Chambert, Finny Kuruvilla, Stacey B. Gabriel, Kristin Ardlie, Jennifer L. Moran, Edward M. Scolnick

Research output: Contribution to journalArticle

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 (US)
Pages (from-to)1117-1129
Number of pages13
JournalMolecular psychiatry
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2011

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Keywords

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

ASJC Scopus subject areas

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

Cite this

Chen, X., Lee, G., Maher, B. S., Fanous, A. H., Chen, J., Zhao, Z., Guo, A., Van Den Oord, E., Sullivan, P. F., Shi, J., Levinson, D. F., Gejman, P. V., Sanders, A., Duan, J., Owen, M. J., Craddock, N. J., O'Donovan, M. C., Blackman, J., Lewis, D., ... Scolnick, E. M. (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