title: Identification of a Bipolar Disorder Vulnerable Gene CHDH at 3p21.1.
abstract: 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.
authors: 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.
authors: Hong
authors: H
authors: Chang
authors: 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.
authors: Lingyi
authors: L
authors: Li
authors: 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.
authors: Tao
authors: T
authors: Peng
authors: Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
authors: Maria
authors: M
authors: Grigoroiu-Serbanescu
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
authors: Sarah E
authors: SE
authors: Bergen
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
authors: Mikael
authors: M
authors: Landén
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Christina M
authors: CM
authors: Hultman
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Andreas J
authors: AJ
authors: Forstner
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors: Jana
authors: J
authors: Strohmaier
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Institute of Genomic Mathematics, University of Bonn, Bonn, Germany.
authors: Julian
authors: J
authors: Hecker
authors: Institute of Psychiatric Phenomics and Genomics, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Thomas G
authors: TG
authors: Schulze
authors: Max Planck Institute of Psychiatry, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors: Bertram
authors: B
authors: Müller-Myhsok
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany.
authors: Andreas
authors: A
authors: Reif
authors: School of Psychiatry, University of New South Wales, Sydney, Australia.|Black Dog Institute, Sydney, Australia.
authors: Philip B
authors: PB
authors: Mitchell
authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland.|Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Jülich, 52425, Jülich, Germany.
authors: Sven
authors: S
authors: Cichon
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors: Markus M
authors: MM
authors: Nöthen
authors: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Faculté de Médecine, Université Paris Est, Créteil, France.|Fondation Fondamental, Créteil, France.
authors: Stéphane
authors: S
authors: Jamain
authors: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Faculté de Médecine, Université Paris Est, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors: Marion
authors: M
authors: Leboyer
authors: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.|AP-HP, Groupe Hospitalier Lariboisière - F. Widal, Pôle de Psychiatrie, Paris, France.|Université Paris Diderot, Paris, France.
authors: Frank
authors: F
authors: Bellivier
authors: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Faculté de Médecine, Université Paris Est, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors: Bruno
authors: B
authors: Etain
authors: Fondation Fondamental, Créteil, France.|Département de Psychiatrie et de Psychologie Clinique, CHU de Nancy, Hôpital Jeanne d'Arc, Toul, France.
authors: Jean-Pierre
authors: JP
authors: Kahn
authors: Inserm U 955, IMRB, Psychiatrie Translationnelle, Créteil, France.|Faculté de Médecine, Université Paris Est, Créteil, France.|Fondation Fondamental, Créteil, France.|AP-HP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy, Pôle de Psychiatrie, Créteil, France.
authors: Chantal
authors: C
authors: Henry
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany.
authors: Marcella
authors: M
authors: Rietschel
authors: 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.
authors: Xiao
authors: X
authors: Xiao
authors: 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.
authors: Ming
authors: http://orcid.org/0000-0002-8197-6552
authors: M
authors: Li
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D050545:Choline Dehydrogenase / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D050545:Choline Dehydrogenase
keywords: Bipolar disorder; CHDH; Cognitive ability; Expression quantitative trait loci (eQTL); Gene expression; Genetic evidence