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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Hong Chang, Kunming Institute of Zoology Chinese Academy of Sciences
  • ,
  • Lingyi Li, Kunming Institute of Zoology Chinese Academy of Sciences
  • ,
  • Tao Peng, Kunming Institute of Zoology Chinese Academy of Sciences
  • ,
  • Maria Grigoroiu-Serbanescu, Alexandru Obregia Clinical Psychiatric Hospital
  • ,
  • Sarah E. Bergen, Broad Institute
  • ,
  • Mikael Landén, Göteborgs Universitet
  • ,
  • Christina M. Hultman, Karolinska Institutet
  • ,
  • Andreas J. Forstner, University of Bonn
  • ,
  • Jana Strohmaier, Universität Heidelberg
  • ,
  • Julian Hecker, University of Bonn
  • ,
  • Thomas G. Schulze, Ludwig-Maximilians-University München
  • ,
  • Bertram Müller-Myhsok, Liverpool University
  • ,
  • Andreas Reif, University Hospital Frankfurt
  • ,
  • Philip B. Mitchell, Black Dog Institute
  • ,
  • Nicholas G. Martin, QIMR Berghofer Medical Research Institute
  • ,
  • Sven Cichon, Forschungszentrum Jülich (FZJ)
  • ,
  • Markus M. Nöthen, University of Bonn
  • ,
  • Stéphane Jamain, Fondation FondaMental
  • ,
  • Marion Leboyer, Pôle de Psychiatrie
  • ,
  • Frank Bellivier, Université Paris—Denis Diderot
  • ,
  • Bruno Etain, Pôle de Psychiatrie
  • ,
  • Jean Pierre Kahn, Hôpital Jeanne d’Arc
  • ,
  • Chantal Henry, Pôle de Psychiatrie
  • ,
  • Marcella Rietschel, Universität Heidelberg
  • ,
  • Lena Backlund
  • ,
  • Louise Frisén
  • ,
  • Catharina Lavebratt
  • ,
  • Martin Schalling
  • ,
  • Urban Ösby
  • ,
  • Thomas W. Mühleisen
  • ,
  • Markus Leber
  • ,
  • Franziska Degenhardt
  • ,
  • Jens Treutlein
  • ,
  • Manuel Mattheisen
  • Andrea Hofmann
  • ,
  • René Breuer
  • ,
  • Sandra Meier
  • ,
  • Stefan Herms
  • ,
  • Per Hoffmann
  • ,
  • André Lacour
  • ,
  • Stephanie H. Witt
  • ,
  • Fabian Streit
  • ,
  • Susanne Lucae
  • ,
  • Wolfgang Maier
  • ,
  • Markus Schwarz
  • ,
  • Helmut Vedder
  • ,
  • Jutta Kammerer-Ciernioch
  • ,
  • Andrea Pfennig
  • ,
  • Michael Bauer
  • ,
  • Martin Hautzinger
  • ,
  • Adam Wright
  • ,
  • Janice M. Fullerton
  • ,
  • Peter R. Schofield
  • ,
  • Grant W. Montgomery
  • ,
  • Sarah E. Medland
  • ,
  • Scott D. Gordon
  • ,
  • Tim Becker
  • ,
  • Johannes Schumacher
  • ,
  • Peter Propping
  • ,
  • Xiao Xiao, Kunming Institute of Zoology Chinese Academy of Sciences
  • ,
  • Ming Li, Kunming Institute of Zoology Chinese Academy of Sciences

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 (Pmeta = 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.

Original languageEnglish
JournalMolecular Neurobiology
Volume54
Issue7
Pages (from-to)5166-5176
Number of pages11
ISSN0893-7648
DOIs
Publication statusPublished - Sep 2017

    Research areas

  • Bipolar disorder, CHDH, Cognitive ability, Expression quantitative trait loci (eQTL), Gene expression, Genetic evidence

See relations at Aarhus University Citationformats

ID: 104660989