Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
27562178
TITLE
Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1.
ABSTRACT
NlmCategory: UNASSIGNED
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.
DATE PUBLISHED
2016 Aug 25
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2016/04/08
accepted 2016/08/05
aheadofprint 2016/08/25
entrez 2016/08/27 06:00
pubmed 2016/08/27 06:00
medline 2016/08/27 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Chang H Chang Hong H Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, People's Republic of China.
Li L Li Lingyi L Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, People's Republic of China.
Peng T Peng Tao T Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, People's Republic of China.
Grigoroiu-Serbanescu M Grigoroiu-Serbanescu Maria M Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
Bergen SE Bergen Sarah E SE Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Landén M Landén Mikael M Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
Hultman CM Hultman Christina M CM Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Forstner AJ Forstner Andreas J AJ Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Strohmaier J Strohmaier Jana J Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Hecker J Hecker Julian J Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
Schulze TG Schulze Thomas G TG Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
Müller-Myhsok B Müller-Myhsok Bertram B Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Reif A Reif Andreas A Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
Mitchell PB Mitchell Philip B PB Black Dog Institute, Sydney, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Cichon S Cichon Sven S Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, 52425, Jülich, Germany.
Nöthen MM Nöthen Markus M MM Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Jamain S Jamain Stéphane S Fondation Fondamental, Créteil, France.
Leboyer M Leboyer Marion M AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
Bellivier F Bellivier Frank F Université Paris Diderot, Paris, France.
Etain B Etain Bruno B AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
Kahn JP Kahn Jean-Pierre JP Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d'Arc, Toul, France.
Henry C Henry Chantal C AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
Rietschel M Rietschel Marcella M Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
Swedish Bipolar Study Group
MooDS Consortium
Xiao X Xiao Xiao X Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, People's Republic of China. xiaoxiao.whu05@gmail.com.
Li M Li Ming M Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, People's Republic of China. limingkiz@mail.kiz.ac.cn.
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Backlund Lena L
Frisén Louise L
Lavebratt Catharina C
Schalling Martin M
Ösby Urban U
Mühleisen ThomasW TW
Leber Markus M
Degenhardt Franziska F
Treutlein Jens J
Mattheisen Manuel M
Hofmann Andrea A
Breuer René R
Meier Sandra S
Herms Stefan S
Hoffmann Per P
Lacour André A
Witt StephanieH SH
Streit Fabian F
Lucae Susanne S
Maier Wolfgang W
Schwarz Markus M
Vedder Helmut H
Kammerer-Ciernioch Jutta J
Pfennig Andrea A
Bauer Michael M
Hautzinger Martin M
Wright Adam A
Fullerton JaniceM JM
Schofield PeterR PR
Montgomery GrantW GW
Medland SarahE SE
Gordon ScottD SD
Becker Tim T
Schumacher Johannes J
Propping Peter P
JOURNAL
VOLUME:
ISSUE:
TITLE: Molecular neurobiology
ISOABBREVIATION: Mol. Neurobiol.
YEAR: 2016
MONTH: Aug
DAY: 25
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1559-1182
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Mol Neurobiol
COUNTRY:
ISSNLINKING: 0893-7648
NLMUNIQUEID: 8900963
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
JOURNAL ARTICLE
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
Bipolar disorder
CHDH
Cognitive ability
Expression quantitative trait loci (eQTL)
Gene expression
Genetic evidence
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's