title: Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.
abstract: Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.
authors.affiliation: 1] State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China [2] University of Chinese Academy of Sciences, Beijing, China.
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authors.initials: M
authors.lastname: Li
authors.affiliation: University of Rochester Flaum Eye Institute, University of Rochester, Rochester, NY, USA.
authors.forename: X-J
authors.initials: XJ
authors.lastname: Luo
authors.affiliation: 1] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany [2] Department of Psychiatry, University of Bonn, Bonn, Germany.
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authors.lastname: Rietschel
authors.affiliation: MRC SGDP Centre, Institute of Psychiatry, King's College London, London, UK.
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authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
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authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
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authors.affiliation: 1] Inserm U 955, IMRB, Psychiatrie Génétique, Créteil, France [2] Fondation Fondamental, Créteil, France [3] Pôle de Psychiatrie, AP-HP, Hôpital H. Mondor-A. Chenevier, Créteil, France [4] Faculté de Médecine, Université Paris Est, Créteil, France.
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authors.lastname: Thompson
authors.affiliation: 1] Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany [2] Department of Genomics, Life and Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany.
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authors.affiliation: 1] Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany [2] Section on Psychiatric Genetics, Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Göttingen, Germany.
authors.forename: T G
authors.initials: TG
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authors.affiliation: Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P F
authors.initials: PF
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authors.affiliation: Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland.
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authors.initials: DW
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authors.affiliation: Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland.
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authors.affiliation: Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland.
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authors.affiliation: Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland.
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authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: C
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authors.affiliation: Imaging Genetics Center, Laboratory of Neuro Imaging, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: L
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authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
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authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: H
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authors.lastname: Shi
authors.affiliation: University of Chinese Academy of Sciences, Beijing, China.
authors.forename: L
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authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.
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authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: D
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authors.affiliation: 1] Inserm U 955, IMRB, Psychiatrie Génétique, Créteil, France [2] Fondation Fondamental, Créteil, France [3] Pôle de Psychiatrie, AP-HP, Hôpital H. Mondor-A. Chenevier, Créteil, France [4] Faculté de Médecine, Université Paris Est, Créteil, France.
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authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
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authors.forename: S
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authors.forename: B
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authors.affiliation: Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD, Australia.
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authors.affiliation: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
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mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D001714:Bipolar Disorder / Q000208:ethnology* / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D009483:Neuropsychological Tests; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger