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The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders

Molecular Psychiatry volume 23, pages 1957–1967 (2018)Cite this article

Abstract

Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 × 10−4; rs6785, P=6.33 × 10−5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 × 10−5; rs6785, P=2.44 × 10−5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein–protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary.

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Acknowledgments

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No., XDB13000000); Chinese Academy of Sciences (CAS) Pioneer Hundred Talents Program (to ML); National Natural Science Foundation of China (81471358); and Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20152530). The Romanian sample recruitment and genotyping was funded by UEFISCDI, Bucharest, Romania (grant no. 89/2012 to MG-S) and by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (grant 01ZX1314A). The data of USA samples used for the analyses described in this manuscript were obtained from dbGaP accession number phs000979.v1.p1; the data of GAIN AA sample used for the analyses described in this manuscript were obtained from dbGaP accession number phs000021.v3.p2 (schizophrenia) and phs000017.v3.p1 (bipolar disorder). This research was supported by the Intramural Research Program of the NIMH (NCT00001260, 900142).

Author information

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, China

    X Xiao, L Wang, L Li, H Chang, Y Wu, Y-G Yao & M Li

  2. Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    C Zhang

  3. Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania

    M Grigoroiu-Serbanescu

  4. Ningbo Kangning Hospital, Ningbo, China

    D Zhou

  5. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    T-F Yuan

  6. Department of Pharmacology, and Provincial Key Laboratory of Pathophysiology in Ningbo University School of Medicine, Ningbo, China

    C Wang

  7. Laboratory for Conservation and Utilization of Bio-Resource, Yunnan University, Kunming, China

    Y Li

  8. State Key Laboratory of Genetic Resources and Evolution, Chinese Academy of Sciences, Kunming, China

    D-D Wu

  9. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Y-G Yao & M Li

Authors
  1. X Xiao
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  2. C Zhang
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  3. M Grigoroiu-Serbanescu
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  4. L Wang
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  5. L Li
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  6. D Zhou
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  7. T-F Yuan
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  8. C Wang
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  9. H Chang
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  10. Y Wu
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  11. Y Li
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  12. D-D Wu
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  13. Y-G Yao
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  14. M Li
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Corresponding authors

Correspondence to C Zhang, M Grigoroiu-Serbanescu or M Li.

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The authors declare no conflict of interest.

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Xiao, X., Zhang, C., Grigoroiu-Serbanescu, M. et al. The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders. Mol Psychiatry 23, 1957–1967 (2018). https://doi.org/10.1038/mp.2017.243

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  • DOI: https://doi.org/10.1038/mp.2017.243

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