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

Artikel i vetenskaplig tidskrift
Författare Hong Chang
Lingyi Li
Tao Peng
Maria Grigoroiu-Serbanescu
Sarah E Bergen
Mikael Landén
Christina M Hultman
Andreas J Forstner
Jana Strohmaier
Julian Hecker
Thomas G Schulze
Bertram Müller-Myhsok
Andreas Reif
Philip B Mitchell
Nicholas G Martin
Sven Cichon
Markus M Nöthen
Stéphane Jamain
Marion Leboyer
Frank Bellivier
Bruno Etain
Jean-Pierre Kahn
Chantal Henry
Marcella Rietschel
Xiao Xiao
Ming Li
Publicerad i Molecular neurobiology
Volym 54
Nummer/häfte 7
Sidor 5166–5176
ISSN 1559-1182
Publiceringsår 2017
Publicerad vid Institutionen för neurovetenskap och fysiologi
Sidor 5166–5176
Språk en
Länkar dx.doi.org/10.1007/s12035-016-0041-...
Ämneskategorier Psykiatri, Klinisk medicin

Sammanfattning

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 × 10(-4)), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 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 ∼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.

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