Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1

Chang, H. and Li, L. and Peng, T. and Grigoroiu-Serbanescu, M. and Bergen, S. E. and Landen, M. and Hultman, C. M. and Forstner, A. J. and Strohmaier, J. and Hecker, J. and Schulze, T. G. and Muller-Myhsok, B. and Reif, A. and Mitchell, P. B. and Martin, N. G. and Cichon, S. and Nothen, M. M. and Jamain, S. and Leboyer, M. and Bellivier, F. and Etain, B. and Kahn, J. P. and Henry, C. and Rietschel, M. and Swedish Bipolar Study, Group and Moo, D. S. Consortium and Xiao, X. and Li, M.. (2016) Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1. Molecular Neurobiology, 54 (7). pp. 5166-5176.

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Official URL: https://edoc.unibas.ch/61534/

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Genome-wide analysis (GWA) is an effective strategy to discover extreme effects surpassing genome-wide significant levels in studying complex disorders; however, when sample size is limited, the true effects may fail to achieve genome-wide significance. In such case, there may be authentic results among the pools of nominal candidates, and an alternative approach is to consider nominal candidates but are replicable across different samples. Here, we found that mRNA expression of the choline dehydrogenase gene (CHDH) was uniformly upregulated in the brains of bipolar disorder (BPD) patients compared with healthy controls across different studies. Follow-up genetic analyses of CHDH variants in multiple independent clinical datasets (including 11,564 cases and 17,686 controls) identified a risk SNP rs9836592 showing consistent associations with BPD (P meta = 5.72 x 10-4), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 x 10-16). These converging results may identify a nominal but true BPD susceptibility gene CHDH. Further exploratory analysis revealed suggestive associations of rs9836592 with childhood intelligence (P = 0.044) and educational attainment (P = 0.0039), a "proxy phenotype" of general cognitive abilities. Intriguingly, the CHDH gene is located at chromosome 3p21.1, a risk region implicated in previous BPD genome-wide association studies (GWAS), but CHDH is lying outside of the core GWAS linkage disequilibrium (LD) region, and our studied SNP rs9836592 is approximately 1.2 Mb 3' downstream of the previous GWAS loci (e.g., rs2251219) with no LD between them; thus, the association observed here is unlikely a reflection of previous GWAS signals. In summary, our results imply that CHDH may play a previously unknown role in the etiology of BPD and also highlight the informative value of integrating gene expression and genetic code in advancing our understanding of its biological basis.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 Apr 2019 16:04
Deposited On:09 Apr 2019 16:04

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