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 × 10−4 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.

Erratum: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

“…These two SNPs showed nominally significant associations among the replication samples (rs2709370 Supplementary Table S5. The odds ratios in the cumulative analysis are comparable with other genes reported as significantly associated with psychiatric disorders in larger meta-analyses 59,60 and exceed the Venice interim criteria for 'small summary' findings. 61 Taken collectively, the association analysis suggests that SNPs in CREB1 may confer risk of BD among Europeans.…”

“…65 Many studies reported psychosis risk genes, although they did not reach genome-wide significance in the initial GWAS samples, they later showed consistent replications in multiple independent samples, such as CMYA5, VRK2 and FGFR2. 59,60,[66][67][68] In small sample sets (<300 cases), association of CREB1 with BD has previously been reported, [69][70][71] with one study finding nominal significant association for the CREB1 variant. However, due to the small sample size and lack of replications, the possibility of falsepositive results in their study could not be excluded.…”

Convergent Lines of Evidence Support LRP8 as a Susceptibility Gene for Psychosis

“…However, even these risk genes can only explain a small portion of the genetic liability, and the missing heritability is still unclear. A recent aggregated analyses [13] indicated that SCZ and BPD are polygenic disorders involving multiple susceptibility variants, with each of them having a tiny effect on the risk, and there may be true findings among those markers passing only nominal significance in the initial GWAS of psychiatric disorders, but later were consistently replicated in independent samples, such as CMYA5 [55], FGFR2 [56], CAMKK2 [57], and CREB1 [30]. Hence, dissection of the GWAS datasets is still valuable for further identification of the risk genes, and we believe this is also one of the most important contributions of GWAS.…”

Genetic studies of schizophrenia: an update

“…With a two-stage design, by integrating data-mining and functional analyses of a selected number of candidates from GWAS datasets, we found that two markers in the CMYA5 gene are associated with SCZ [31] ; one of the markers (rs10043986) changes a proline to leucine in the protein sequence. Using a convergent functional genomics approach, which utilizes poly-evidence scoring and pathway analyses, Ayalew et al identified several genes involved in SCZ, including DISC1 and TCF4 [32] .…”