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Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

Molecular Psychiatry volume 19, pages 452–461 (2014)Cite this article

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A Corrigendum to this article was published on 14 May 2013

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.

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Acknowledgements

We acknowledge the Bipolar Disorder Working Group of Psychiatric GWAS Consortium for their efforts. We are deeply grateful for Stacy Steinberg, Hreinn Stefansson, Kari Stefansson (deCODE genetics, Reykjavik, Iceland) and Engilbert Sigurdsson (Landspitali University Hospital, Reykjavík, Iceland) for their results in the Icelandic samples, Angelika Erhardt (Max Planck Institute of Psychiatry, Kraepelinstr, Munich, Germany) for her assistance in this study, Andrew Willden (Kunming Institute of Zoology, China) for the language editing of the manuscript. We wish to thank Xiaosen Guo, Shanshan Dong and Jun Wang (Shenzhen Key Laboratory of Transomics Biotechnologies, BGI-Shenzhen, China) for providing sequence data of CREB1 from the 1000-Human-Genome project. We would like to thank Daniel R. Weinberger (Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, USA) for his very helpful review of the manuscript. This work was supported by grants from the National 973 project of China (2011CBA00401), the National Natural Science Foundation of China (U1202225, 31130051 and 31071101), the German Federal Ministry of Education and Research (BMBF), the National Genome Research Network (NGFN), and the Integrated Genome Research Network (IG) MooDS (grant 01GS08144 to SC and MMR, grant 01GS08147 to MR and TGS).

Author information

Author notes

  1. M Li and X-j Luo: These authors contributed equally to this work.

  2. A full list of the members is provided in the Supplementary Data.

  3. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

  4. A full list of the members in the consortium can be found in their original studies.

Authors and Affiliations

  1. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    M Li, L Shi, Q Lin, H Shi & B Su

  2. University of Chinese Academy of Sciences, Beijing, China

    M Li & L Gan

  3. University of Rochester Flaum Eye Institute, University of Rochester, Rochester, NY, USA

    X-j Luo

  4. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Mannheim, Germany

    M Rietschel & T G Schulze

  5. Department of Psychiatry, University of Bonn, Bonn, Germany

    M Rietschel & H Walter

  6. MRC SGDP Centre, Institute of Psychiatry, King’s College London, London, UK

    C M Lewis

  7. Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    M Mattheisen

  8. Max Planck Institute of Psychiatry, Munich, Germany

    B Müller-Myhsok & D Czamara

  9. Inserm U 955, IMRB, Psychiatrie Génétique, Créteil, France

    S Jamain, M Leboyer, C Henry, B Etain & F Bellivier

  10. Fondation Fondamental, Créteil, France

    S Jamain, M Leboyer, C Henry, B Etain & F Bellivier

  11. Pôle de Psychiatrie, AP-HP, Hôpital H. Mondor-A. Chenevier, Créteil, France

    M Leboyer, C Henry & B Etain

  12. Faculté de Médecine, Université Paris Est, Créteil, France

    M Leboyer & C Henry

  13. Section of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden

    M Landén

  14. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden

    M Landén & C Hultman

  15. Department of Neurology, Imaging Genetics Center, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    P M Thompson, A W Toga, J L Stein & D P Hibar

  16. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

    S Cichon

  17. Department of Genomics, Life and Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany

    S Cichon & M M Nöthen

  18. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    M M Nöthen

  19. Department of Psychiatry and Psychotherapy, Section on Psychiatric Genetics, University Medical Center, Georg-August-University, Göttingen, Germany

    T G Schulze

  20. Departments of Genetics, Psychiatry and Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    P F Sullivan

  21. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    S E Bergen

  22. Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    S E Bergen

  23. 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

    G Donohoe, D W Morris, A Hargreaves, M Gill & A Corvin

  24. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    A Meyer-Lindenberg

  25. Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA

    J C Bis

  26. Department of Radiology and Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

    M A Ikram

  27. The Netherlands Consortium of Healthy Aging, Leiden, The Netherlands

    M A Ikram

  28. Brown Foundation Institute of Molecular Medicine and Human Genetics Center School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

    M Fornage

  29. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    S Debette & S Seshadri

  30. Institut National de la Santé et de la Recherche Médicale (INSERM), U708, Neuroepidemiology, Paris, France

    S Debette

  31. Department of Epidemiology, University of Versailles Saint-Quentin-en-Yvelines, Paris, France

    S Debette

  32. Laboratory of Neurogenetics, Intramural Research Program, National Institute of Aging, NIH, Bethesda, MD, USA

    L J Launer

  33. The National, Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    S Seshadri

  34. Department of Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany

    S Erk, H Walter & A Heinz

  35. Division of Mind and Brain Research, Charité Universitätsmedizin Berlin, Berlin, Germany

    S Erk & H Walter

  36. AP-HP, Hôpital St-Louis-Lariboisière-F Widal, Service Universitaire de Psychiatrie, Paris, France

    F Bellivier

  37. Faculté de Médecine, Université Denis Diderot, Paris, France

    F Bellivier

  38. Department of Neurology, Neurogenetics Program, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    J L Stein

  39. Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD, Australia

    S E Medland, N G Martin & M J Wright

  40. Quantitative Genetics Laboratory, Queensland Institute of Medical Research, Brisbane, QLD, Australia

    S E Medland

  41. Broad Institute of Harvard and MIT, Boston, MA, USA

    S E Medland

  42. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    A Arias Vasquez & B Franke

  43. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    A Arias Vasquez & B Franke

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  1. M Li
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  2. X-j Luo
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Consortia

MooDS Bipolar Consortium

The Swedish Bipolar Study Group

The Alzheimer’s Disease Neuroimaging Initiative

ENIGMA Consortium

CHARGE Consortium

Corresponding author

Correspondence to B Su.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Li, M., Luo, Xj., Rietschel, M. et al. Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility. Mol Psychiatry 19, 452–461 (2014). https://doi.org/10.1038/mp.2013.37

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  • DOI: https://doi.org/10.1038/mp.2013.37

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