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, M. 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, Michael C. O'Donovan, George K. Kirov, Nick J. Craddock, Peter A. Holmans, Nigel M. Williams, Lyudmila Georgieva, Ivan Nikolov, N. Norton, H. Williams, Draga Toncheva, Vihra Milanova, Christina M. Hultman, Paul Lichtenstein, Emma F. Thelander, Patrick Sullivan, Derek W. Morris, Colm T. O'Dushlaine, Elaine Kenny, Emma M. Quinn, Michael Gill, Aiden Corvin, Andrew McQuillin, Khalid Choudhury, Susmita Datta, Jonathan Pimm, Srinivasa Thirumalai, Vinay Puri, Robert Krasucki, Jacob Lawrence, Digby Quested, Nicholas Bass, Hugh Gurling, Caroline Crombie, Gillian Fraser, Soh Leh Kuan, Nicholas Walker, David St Clair, Douglas H.R. Blackwood, Walter J. Muir, Kevin A. McGhee, Ben Pickard, Pat Malloy, Alan W. Maclean, Margaret Van Beck, Naomi R. Wray, Stuart Macgregor, Peter M. Visscher, Michele T. Pato, Helena Medeiros, Frank Middleton, Celia Carvalho, Christopher Morley, Ayman Fanous, David Conti, James A. Knowles, Carlos Paz Ferreira, Antonio Macedo, M. Helena Azevedo, Carlos N. Pato, Jennifer L. Stone, Douglas M. Ruderfer, Andrew N. Kirby, Manuel A.R. Ferreira, Mark J. Daly, Shaun M. Purcell, Pamela Sklar, Kimberly Chambert, Finny Kuruvilla, Stacey B. Gabriel, Kristin Ardlie, Jennifer L. Moran, Edward M. Scolnick

Research output: Contribution to journalArticle

50 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 (US)
Pages (from-to)1117-1129
Number of pages13
JournalMolecular Psychiatry
Volume16
Issue number11
DOIs
StatePublished - Nov 1 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
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia. / 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.; Kirov, G. K.; Qin, W.; Schwab, S.; Wildenauer, D.; Chowdari, K.; Nimgaonkar, V.; Straub, R. E.; Weinberger, D. R.; O'Neill, F. A.; Walsh, D.; Bronstein, M.; Darvasi, A.; Lencz, T.; Malhotra, A. K.; Rujescu, D.; Giegling, I.; Werge, T.; Hansen, T.; Ingason, A.; Nöethen, M. M.; Rietschel, M.; Cichon, S.; Djurovic, S.; Andreassen, O. A.; Cantor, R. M.; Ophoff, R.; Corvin, A.; Morris, D. W.; Gill, M.; Pato, C. N.; Pato, M. T.; Macedo, A.; Gurling, H. M.D.; McQuillin, A.; Pimm, J.; Hultman, C.; Lichtenstein, P.; Sklar, P.; Purcell, S. M.; Scolnick, E.; St Clair, D.; Blackwood, D. H.R.; Kendler, K. S.; Kahn, René S.; Linszen, Don H.; Van Os, Jim; Wiersma, Durk; Bruggeman, Richard; Cahn, Wiepke; De Haan, Lieuwe; Krabbendam, Lydia; Myin-Germeys, Inez; O'Donovan, Michael C.; Kirov, George K.; Craddock, Nick J.; Holmans, Peter A.; Williams, Nigel M.; Georgieva, Lyudmila; Nikolov, Ivan; Norton, N.; Williams, H.; Toncheva, Draga; Milanova, Vihra; Hultman, Christina M.; Lichtenstein, Paul; Thelander, Emma F.; Sullivan, Patrick; Morris, Derek W.; O'Dushlaine, Colm T.; Kenny, Elaine; Quinn, Emma M.; Gill, Michael; Corvin, Aiden; McQuillin, Andrew; Choudhury, Khalid; Datta, Susmita; Pimm, Jonathan; Thirumalai, Srinivasa; Puri, Vinay; Krasucki, Robert; Lawrence, Jacob; Quested, Digby; Bass, Nicholas; Gurling, Hugh; Crombie, Caroline; Fraser, Gillian; Kuan, Soh Leh; Walker, Nicholas; St Clair, David; Blackwood, Douglas H.R.; Muir, Walter J.; McGhee, Kevin A.; Pickard, Ben; Malloy, Pat; Maclean, Alan W.; Van Beck, Margaret; Wray, Naomi R.; Macgregor, Stuart; Visscher, Peter M.; Pato, Michele T.; Medeiros, Helena; Middleton, Frank; Carvalho, Celia; Morley, Christopher; Fanous, Ayman; Conti, David; Knowles, James A.; Ferreira, Carlos Paz; Macedo, Antonio; Azevedo, M. Helena; Pato, Carlos N.; Stone, Jennifer L.; Ruderfer, Douglas M.; Kirby, Andrew N.; Ferreira, Manuel A.R.; Daly, Mark J.; Purcell, Shaun M.; Sklar, Pamela; Chambert, Kimberly; Kuruvilla, Finny; Gabriel, Stacey B.; Ardlie, Kristin; Moran, Jennifer L.; Scolnick, Edward M.

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

Research output: Contribution to journalArticle

Chen, X, Lee, G, Maher, BS, Fanous, AH, Chen, J, Zhao, Z, Guo, A, Van Den Oord, E, Sullivan, PF, Shi, J, Levinson, DF, Gejman, PV, Sanders, A, Duan, J, Owen, MJ, Craddock, NJ, O'Donovan, MC, Blackman, J, Lewis, D, Kirov, GK, Qin, W, Schwab, S, Wildenauer, D, Chowdari, K, Nimgaonkar, V, Straub, RE, Weinberger, DR, O'Neill, FA, Walsh, D, Bronstein, M, Darvasi, A, Lencz, T, Malhotra, AK, Rujescu, D, Giegling, I, Werge, T, Hansen, T, Ingason, A, Nöethen, MM, Rietschel, M, Cichon, S, Djurovic, S, Andreassen, OA, Cantor, RM, Ophoff, R, Corvin, A, Morris, DW, Gill, M, Pato, CN, Pato, MT, Macedo, A, Gurling, HMD, McQuillin, A, Pimm, J, Hultman, C, Lichtenstein, P, Sklar, P, Purcell, SM, Scolnick, E, St Clair, D, Blackwood, DHR, Kendler, KS, Kahn, RS, Linszen, DH, Van Os, J, Wiersma, D, Bruggeman, R, Cahn, W, De Haan, L, Krabbendam, L, Myin-Germeys, I, O'Donovan, MC, Kirov, GK, Craddock, NJ, Holmans, PA, Williams, NM, Georgieva, L, Nikolov, I, Norton, N, Williams, H, Toncheva, D, Milanova, V, Hultman, CM, Lichtenstein, P, Thelander, EF, Sullivan, P, Morris, DW, O'Dushlaine, CT, Kenny, E, Quinn, EM, Gill, M, Corvin, A, McQuillin, A, Choudhury, K, Datta, S, Pimm, J, Thirumalai, S, Puri, V, Krasucki, R, Lawrence, J, Quested, D, Bass, N, Gurling, H, Crombie, C, Fraser, G, Kuan, SL, Walker, N, St Clair, D, Blackwood, DHR, Muir, WJ, McGhee, KA, Pickard, B, Malloy, P, Maclean, AW, Van Beck, M, Wray, NR, Macgregor, S, Visscher, PM, Pato, MT, Medeiros, H, Middleton, F, Carvalho, C, Morley, C, Fanous, A, Conti, D, Knowles, JA, Ferreira, CP, Macedo, A, Azevedo, MH, Pato, CN, Stone, JL, Ruderfer, DM, Kirby, AN, Ferreira, MAR, Daly, MJ, Purcell, SM, Sklar, P, Chambert, K, Kuruvilla, F, Gabriel, SB, Ardlie, K, Moran, JL & Scolnick, EM 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
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. ; Kirov, G. K. ; Qin, W. ; Schwab, S. ; Wildenauer, D. ; Chowdari, K. ; Nimgaonkar, V. ; Straub, R. E. ; Weinberger, D. R. ; O'Neill, F. A. ; Walsh, D. ; Bronstein, M. ; Darvasi, A. ; Lencz, T. ; Malhotra, A. K. ; Rujescu, D. ; Giegling, I. ; Werge, T. ; Hansen, T. ; Ingason, A. ; Nöethen, M. M. ; Rietschel, M. ; Cichon, S. ; Djurovic, S. ; Andreassen, O. A. ; Cantor, R. M. ; Ophoff, R. ; Corvin, A. ; Morris, D. W. ; Gill, M. ; Pato, C. N. ; Pato, M. T. ; Macedo, A. ; Gurling, H. M.D. ; McQuillin, A. ; Pimm, J. ; Hultman, C. ; Lichtenstein, P. ; Sklar, P. ; Purcell, S. M. ; Scolnick, E. ; St Clair, D. ; Blackwood, D. H.R. ; Kendler, K. S. ; Kahn, René S. ; Linszen, Don H. ; Van Os, Jim ; Wiersma, Durk ; Bruggeman, Richard ; Cahn, Wiepke ; De Haan, Lieuwe ; Krabbendam, Lydia ; Myin-Germeys, Inez ; O'Donovan, Michael C. ; Kirov, George K. ; Craddock, Nick J. ; Holmans, Peter A. ; Williams, Nigel M. ; Georgieva, Lyudmila ; Nikolov, Ivan ; Norton, N. ; Williams, H. ; Toncheva, Draga ; Milanova, Vihra ; Hultman, Christina M. ; Lichtenstein, Paul ; Thelander, Emma F. ; Sullivan, Patrick ; Morris, Derek W. ; O'Dushlaine, Colm T. ; Kenny, Elaine ; Quinn, Emma M. ; Gill, Michael ; Corvin, Aiden ; McQuillin, Andrew ; Choudhury, Khalid ; Datta, Susmita ; Pimm, Jonathan ; Thirumalai, Srinivasa ; Puri, Vinay ; Krasucki, Robert ; Lawrence, Jacob ; Quested, Digby ; Bass, Nicholas ; Gurling, Hugh ; Crombie, Caroline ; Fraser, Gillian ; Kuan, Soh Leh ; Walker, Nicholas ; St Clair, David ; Blackwood, Douglas H.R. ; Muir, Walter J. ; McGhee, Kevin A. ; Pickard, Ben ; Malloy, Pat ; Maclean, Alan W. ; Van Beck, Margaret ; Wray, Naomi R. ; Macgregor, Stuart ; Visscher, Peter M. ; Pato, Michele T. ; Medeiros, Helena ; Middleton, Frank ; Carvalho, Celia ; Morley, Christopher ; Fanous, Ayman ; Conti, David ; Knowles, James A. ; Ferreira, Carlos Paz ; Macedo, Antonio ; Azevedo, M. Helena ; Pato, Carlos N. ; Stone, Jennifer L. ; Ruderfer, Douglas M. ; Kirby, Andrew N. ; Ferreira, Manuel A.R. ; Daly, Mark J. ; Purcell, Shaun M. ; Sklar, Pamela ; Chambert, Kimberly ; Kuruvilla, Finny ; Gabriel, Stacey B. ; Ardlie, Kristin ; Moran, Jennifer L. ; Scolnick, Edward M. / 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.
@article{fa2316d98bbe4de39a64ed20ae6b89bf,
title = "GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia",
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.",
keywords = "association study, cardiomyopathy, GWA data mining, meta-analysis, schizophrenia",
author = "X. Chen and G. Lee and Maher, {B. S.} and Fanous, {A. H.} and J. Chen and Z. Zhao and A. Guo and {Van Den Oord}, E. and Sullivan, {P. F.} and J. Shi and Levinson, {D. F.} and Gejman, {P. V.} and A. Sanders and J. Duan and Owen, {M. J.} and Craddock, {N. J.} and O'Donovan, {M. C.} and J. Blackman and D. Lewis and Kirov, {G. K.} and W. Qin and S. Schwab and D. Wildenauer and K. Chowdari and V. Nimgaonkar and Straub, {R. E.} and Weinberger, {D. R.} and O'Neill, {F. A.} and D. Walsh and M. Bronstein and A. Darvasi and T. Lencz and Malhotra, {A. K.} and D. Rujescu and I. Giegling and T. Werge and T. Hansen and A. Ingason and N{\"o}ethen, {M. M.} and M. Rietschel and S. Cichon and S. Djurovic and Andreassen, {O. A.} and Cantor, {R. M.} and R. Ophoff and A. Corvin and Morris, {D. W.} and M. Gill and Pato, {C. N.} and Pato, {M. T.} and A. Macedo and Gurling, {H. M.D.} and A. McQuillin and J. Pimm and C. Hultman and P. Lichtenstein and P. Sklar and Purcell, {S. M.} and E. Scolnick and {St Clair}, D. and Blackwood, {D. H.R.} and Kendler, {K. S.} and Kahn, {Ren{\'e} S.} and Linszen, {Don H.} and {Van Os}, Jim and Durk Wiersma and Richard Bruggeman and Wiepke Cahn and {De Haan}, Lieuwe and Lydia Krabbendam and Inez Myin-Germeys and O'Donovan, {Michael C.} and Kirov, {George K.} and Craddock, {Nick J.} and Holmans, {Peter A.} and Williams, {Nigel M.} and Lyudmila Georgieva and Ivan Nikolov and N. Norton and H. Williams and Draga Toncheva and Vihra Milanova and Hultman, {Christina M.} and Paul Lichtenstein and Thelander, {Emma F.} and Patrick Sullivan and Morris, {Derek W.} and O'Dushlaine, {Colm T.} and Elaine Kenny and Quinn, {Emma M.} and Michael Gill and Aiden Corvin and Andrew McQuillin and Khalid Choudhury and Susmita Datta and Jonathan Pimm and Srinivasa Thirumalai and Vinay Puri and Robert Krasucki and Jacob Lawrence and Digby Quested and Nicholas Bass and Hugh Gurling and Caroline Crombie and Gillian Fraser and Kuan, {Soh Leh} and Nicholas Walker and {St Clair}, David and Blackwood, {Douglas H.R.} and Muir, {Walter J.} and McGhee, {Kevin A.} and Ben Pickard and Pat Malloy and Maclean, {Alan W.} and {Van Beck}, Margaret and Wray, {Naomi R.} and Stuart Macgregor and Visscher, {Peter M.} and Pato, {Michele T.} and Helena Medeiros and Frank Middleton and Celia Carvalho and Christopher Morley and Ayman Fanous and David Conti and Knowles, {James A.} and Ferreira, {Carlos Paz} and Antonio Macedo and Azevedo, {M. Helena} and Pato, {Carlos N.} and Stone, {Jennifer L.} and Ruderfer, {Douglas M.} and Kirby, {Andrew N.} and Ferreira, {Manuel A.R.} and Daly, {Mark J.} and Purcell, {Shaun M.} and Pamela Sklar and Kimberly Chambert and Finny Kuruvilla and Gabriel, {Stacey B.} and Kristin Ardlie and Moran, {Jennifer L.} and Scolnick, {Edward M.}",
year = "2011",
month = "11",
day = "1",
doi = "10.1038/mp.2010.96",
language = "English (US)",
volume = "16",
pages = "1117--1129",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia

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, M. 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 - Morris, D. W.

AU - Gill, M.

AU - Pato, C. N.

AU - Pato, M. T.

AU - Macedo, A.

AU - Gurling, H. M.D.

AU - McQuillin, A.

AU - Pimm, J.

AU - Hultman, C.

AU - Lichtenstein, P.

AU - Sklar, P.

AU - Purcell, S. M.

AU - Scolnick, E.

AU - St Clair, D.

AU - Blackwood, D. H.R.

AU - Kendler, K. S.

AU - Kahn, René S.

AU - Linszen, Don H.

AU - Van Os, Jim

AU - Wiersma, Durk

AU - Bruggeman, Richard

AU - Cahn, Wiepke

AU - De Haan, Lieuwe

AU - Krabbendam, Lydia

AU - Myin-Germeys, Inez

AU - O'Donovan, Michael C.

AU - Kirov, George K.

AU - Craddock, Nick J.

AU - Holmans, Peter A.

AU - Williams, Nigel M.

AU - Georgieva, Lyudmila

AU - Nikolov, Ivan

AU - Norton, N.

AU - Williams, H.

AU - Toncheva, Draga

AU - Milanova, Vihra

AU - Hultman, Christina M.

AU - Lichtenstein, Paul

AU - Thelander, Emma F.

AU - Sullivan, Patrick

AU - Morris, Derek W.

AU - O'Dushlaine, Colm T.

AU - Kenny, Elaine

AU - Quinn, Emma M.

AU - Gill, Michael

AU - Corvin, Aiden

AU - McQuillin, Andrew

AU - Choudhury, Khalid

AU - Datta, Susmita

AU - Pimm, Jonathan

AU - Thirumalai, Srinivasa

AU - Puri, Vinay

AU - Krasucki, Robert

AU - Lawrence, Jacob

AU - Quested, Digby

AU - Bass, Nicholas

AU - Gurling, Hugh

AU - Crombie, Caroline

AU - Fraser, Gillian

AU - Kuan, Soh Leh

AU - Walker, Nicholas

AU - St Clair, David

AU - Blackwood, Douglas H.R.

AU - Muir, Walter J.

AU - McGhee, Kevin A.

AU - Pickard, Ben

AU - Malloy, Pat

AU - Maclean, Alan W.

AU - Van Beck, Margaret

AU - Wray, Naomi R.

AU - Macgregor, Stuart

AU - Visscher, Peter M.

AU - Pato, Michele T.

AU - Medeiros, Helena

AU - Middleton, Frank

AU - Carvalho, Celia

AU - Morley, Christopher

AU - Fanous, Ayman

AU - Conti, David

AU - Knowles, James A.

AU - Ferreira, Carlos Paz

AU - Macedo, Antonio

AU - Azevedo, M. Helena

AU - Pato, Carlos N.

AU - Stone, Jennifer L.

AU - Ruderfer, Douglas M.

AU - Kirby, Andrew N.

AU - Ferreira, Manuel A.R.

AU - Daly, Mark J.

AU - Purcell, Shaun M.

AU - Sklar, Pamela

AU - Chambert, Kimberly

AU - Kuruvilla, Finny

AU - Gabriel, Stacey B.

AU - Ardlie, Kristin

AU - Moran, Jennifer L.

AU - Scolnick, Edward M.

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.

KW - association study

KW - cardiomyopathy

KW - GWA data mining

KW - meta-analysis

KW - schizophrenia

UR - http://www.scopus.com/inward/record.url?scp=79958143783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79958143783&partnerID=8YFLogxK

U2 - 10.1038/mp.2010.96

DO - 10.1038/mp.2010.96

M3 - Article

C2 - 20838396

AN - SCOPUS:79958143783

VL - 16

SP - 1117

EP - 1129

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 11

ER -