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

Li, M. and Luo, X.-J. and Rietschel, M. and Lewis, C. M. and Mattheisen, M. and Müller-Myhsok, B. and Jamain, S. and Leboyer, M. and Landén, M. and Thompson, P. M. and Cichon, S. and Nöthen, M. M. and Schulze, T. G. and Sullivan, P. F. and Bergen, S. E. and Donohoe, G. and Morris, D. W. and Hargreaves, A. and Gill, M. and Corvin, A. and Hultman, C. and Toga, A. W. and Shi, L. and Lin, Q. and Shi, H. and Gan, L. and Meyer-Lindenberg, A. and Czamara, D. and Henry, C. and Etain, B. and Bis, J. C. and Ikram, M. A. and Fornage, M. and Debette, S. and Launer, L. J. and Seshadri, S. and Erk, S. and Walter, H. and Heinz, A. and Bellivier, F. and Stein, J. L. and Medland, S. E. and Arias Vasquez, A. and Hibar, D. P. and Franke, B. and Martin, N. G. and Wright, M. J. and MooDS Bipolar Consortium, and Swedish Bipolar Study Group, and Alzheimer's Disease Neuroimaging Initiative, and Enigma Consortium, and Charge Consortium, and Su, B.. (2014) 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, 19 (4). pp. 452-461.

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Official URL: https://edoc.unibas.ch/61567/

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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 x 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 x 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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Human Genetics (Cichon)
UniBasel Contributors:Cichon, Sven
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Dec 2020 08:09
Deposited On:16 Dec 2020 08:09

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