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).
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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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