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| PMID |
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| TITLE |
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| Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1. |
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| ABSTRACT |
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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 × 10 ), and the risk allele indicated an increased CHDH expression in multiple neuronal tissues (lowest P = 6.70 × 10 ). 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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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2016/04/08 |
| accepted |
2016/08/05 |
| pubmed |
2016/08/27 06:00 |
| medline |
2018/05/11 06:00 |
| entrez |
2016/08/27 06:00 |
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| 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. |
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| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Backlund |
Lena |
L |
|
| Frisén |
Louise |
L |
|
| Lavebratt |
Catharina |
C |
|
| Schalling |
Martin |
M |
|
| Ösby |
Urban |
U |
|
| Mühleisen |
Thomas W |
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 |
Stephanie H |
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 |
Janice M |
JM |
|
| Schofield |
Peter R |
PR |
|
| Montgomery |
Grant W |
GW |
|
| Medland |
Sarah E |
SE |
|
| Gordon |
Scott D |
SD |
|
| Becker |
Tim |
T |
|
| Schumacher |
Johannes |
J |
|
| Propping |
Peter |
P |
|
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| JOURNAL |
|
| VOLUME: 54 |
| ISSUE: 7 |
| TITLE: Molecular neurobiology |
| ISOABBREVIATION: Mol Neurobiol |
| YEAR: 2017 |
| MONTH: 09 |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1559-1182 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
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| MEDLINETA: Mol Neurobiol |
| COUNTRY: United States |
| ISSNLINKING: 0893-7648 |
| NLMUNIQUEID: 8900963 |
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| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, Non-U.S. Gov't |
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| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
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| GENERAL NOTE |
|
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| KEYWORDS |
|
| KEYWORD |
| Bipolar disorder |
| CHDH |
| Cognitive ability |
| Expression quantitative trait loci (eQTL) |
| Gene expression |
| Genetic evidence |
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| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Adult |
|
| Bipolar Disorder |
genetics |
| Brain |
metabolism |
| Choline Dehydrogenase |
genetics |
| Chromosomes, Human, Pair 3 |
genetics |
| Female |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Genome-Wide Association Study |
methods |
| Genotype |
methods |
| Humans |
methods |
| Linkage Disequilibrium |
methods |
| Male |
methods |
| Phenotype |
methods |
| Polymorphism, Single Nucleotide |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| EC 1.1.99.1 |
Choline Dehydrogenase |
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| OTHER ID's |
|
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