You are here

Mol Psychiatry DOI:10.1038/mp.2010.96

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

Publication TypeJournal Article
Year of Publication2011
AuthorsChen, 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, Noethen, 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
Corporate AuthorsGROUP Investigators, International Schizophrenia Consortium
JournalMol Psychiatry
Volume16
Issue11
Pages1117-29
Date Published2011 Nov
ISSN1476-5578
KeywordsAfrican Americans, Carrier Proteins, Case-Control Studies, Data Mining, Dystrophin-Associated Proteins, European Continental Ancestry Group, Genome-Wide Association Study, Germany, Humans, Ireland, Jews, Linkage Disequilibrium, Muscle Proteins, Pennsylvania, Polymorphism, Single Nucleotide, Risk, 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, r(2)=0.008; rs10043986-rs4704591, r(2)=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(-4) and 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.

DOI10.1038/mp.2010.96
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/20838396?dopt=Abstract

Alternate JournalMol. Psychiatry
PubMed ID20838396
PubMed Central IDPMC3443634
Grant ListR01 MH074027 / MH / NIMH NIH HHS / United States
N01 MH900001 / MH / NIMH NIH HHS / United States
R01 MH078075 / MH / NIMH NIH HHS / United States
R01 MH041953-10 / MH / NIMH NIH HHS / United States
R10 MH056242 / MH / NIMH NIH HHS / United States
R01 MH041953-09A2 / MH / NIMH NIH HHS / United States
R01 MH041953-17 / MH / NIMH NIH HHS / United States
MH63480 / MH / NIMH NIH HHS / United States
R01 MH041953-14 / MH / NIMH NIH HHS / United States
MH074027 / MH / NIMH NIH HHS / United States
/ / Medical Research Council / United Kingdom
R01 MH041953-16 / MH / NIMH NIH HHS / United States
MH078075 / MH / NIMH NIH HHS / United States
R01 MH041953-11 / MH / NIMH NIH HHS / United States
R01 MH041953-08S1 / MH / NIMH NIH HHS / United States
R01 MH041953 / MH / NIMH NIH HHS / United States
R01 MH041953-13 / MH / NIMH NIH HHS / United States
MH41953 / MH / NIMH NIH HHS / United States
R01 MH041953-15 / MH / NIMH NIH HHS / United States
R01 MH063480 / MH / NIMH NIH HHS / United States
MH56242 / MH / NIMH NIH HHS / United States
R01 MH056242 / MH / NIMH NIH HHS / United States
G0800509 / / Medical Research Council / United Kingdom
R01 MH041953-12 / MH / NIMH NIH HHS / United States
/ / Wellcome Trust / United Kingdom