Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility
Year: 2013
Type: article
Study design: Observational Study
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.
Source: Molecular Psychiatry
DOI: 10.1038/mp.2013.37
Authors: M Li, X-j Luo, M Rietschel, C M Lewis, M Mattheisen, B Müller-Myhsok, S Jamain, M Leboyer, M Landén, P M Thompson, S Cichon, M M Nöthen, T G Schulze, P F Sullivan, S E Bergen, G Donohoe, D W Morris, A Hargreaves, M Gill, A Corvin, C Hultman, A W Toga, L Shi, Q Lin, H Shi, L Gan, A Meyer-Lindenberg, D Czamara, C Henry, B Etain, J C Bis, M A Ikram, M Fornage, S Debette, L J Launer, S Seshadri, S Erk, H Walter, A Heinz, F Bellivier, J L Stein, S E Medland, A Arias Vasquez, D P Hibar, B Franke, N G Martin, M J Wright, The Swedish Bipolar Study Group, The Alzheimer’s Disease Neuroimaging Initiative, B Su
Institutions: Kunming Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, State Key Laboratory of Genetic Resources and Evolution, University of Rochester Medicine, University of Rochester, University of Bonn, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, King's College London, Brigham and Women's Hospital, Harvard University, Max Planck Institute of Psychiatry, Inserm, Fondation FondaMental, Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, Assistance Publique – Hôpitaux de Paris, Karolinska Institutet, University of Gothenburg, University of California, Los Angeles, Forschungszentrum Jülich, German Center for Neurodegenerative Diseases, University of Göttingen, University of North Carolina at Chapel Hill, Broad Institute, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Massachusetts Institute of Technology, Trinity College Dublin, St. James's Hospital, Hôpital Albert-Chenevier, University of Washington, Erasmus MC, Netherlands Consortium for Healthy Ageing, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Boston University, Université de Versailles Saint-Quentin-en-Yvelines, National Institutes of Health, Framingham Heart Study, Charité – Universitätsmedizin Berlin, Hôpital Saint-Louis, Université Paris Diderot, QIMR Berghofer Medical Research Institute, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: Johns Hopkins University, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, Lundbeckfonden, Landspítali Háskólasjúkrahús, Kunming Institute of Zoology, Chinese Academy of Sciences, National Institute on Aging, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: UC Davis Alzheimer's Disease Core Center, CHARGE: Identifying Risk & Protective SNV for AD in ADSP Case-control Sample, G2005830010, G214445032, Genetic influences on the brain: A twin imaging study, G2717198908, Verbundprojekt: Molekulare Ursachen von Affektiven Störungen und Schizophrenie 'MOODS' -TP 5,6, Verbundprojekt: Molekulare Ursachen von Affektiven Störungen und Schizophrenie 'Moods' - Teilprojekt : 1, 3, 4, 6, 7, 9, 12, 14, 灵长类大脑进化关键基因的功能研究, Epidemiology of Dementia in the Framingham Study, Precursors of Stroke Incidence and Prognosis, National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)
OpenAlex ID: W2157601113