Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.
Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.
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DOI：
10.1038/mp.2013.37
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发表时间：
2014-04
影响因子：
11
通讯作者：
Su, B.
中科院分区：
文献类型：
--
作者：
Li, M.;Luo, X-j;Rietschel, M.;Lewis, C. M.;Mattheisen, M.;Mueller-Myhsok, B.;Jamain, S.;Leboyer, M.;Landen, M.;Thompson, P. M.;Cichon, S.;Noethen, M. M.;Schulze, T. G.;Sullivan, P. F.;Bergen, S. E.;Donohoe, G.;Morris, D. W.;Hargreaves, A.;Gill, M.;Corvin, A.;Hultman, C.;Toga, A. W.;Shi, L.;Lin, Q.;Shi, H.;Gan, L.;Meyer-Lindenberg, A.;Czamara, D.;Henry, C.;Etain, B.;Bis, J. C.;Ikram, M. A.;Fornage, M.;Debette, S.;Launer, L. J.;Seshadri, S.;Erk, S.;Walter, H.;Heinz, A.;Bellivier, F.;Stein, J. L.;Medland, S. E.;Vasquez, A. Arias;Hibar, D. P.;Franke, B.;Martin, N. G.;Wright, M. J.;Su, B.
双相情感障碍（BD）是一种多基因疾病，与重性抑郁症（MDD）有大量的遗传危险因素。遗传分析已经报道了许多BD易感基因，而一些变体，如CACNA1C中的单核苷酸多态性（SNP）已被成功复制，许多其他人没有，随后它们对中间表型的影响无法验证。在此，我们研究了一组独立的欧洲血统BD样本组（共64 888例受试者）中的MDD相关基因CREB 1，并确定了与BD显著相关的多个SNP（最显著的是SNP rs6785[A]，P = 6.32 × 10−5，比值比（OR）= 1.090）。然后对健康欧洲人的BD中间表型（包括海马体积、海马功能和认知能力）的风险SNP进行进一步分析。我们的研究结果表明，风险SNP与海马体积和海马功能显著相关，风险等位基因显示海马体积减小，左侧海马激活减少，进一步证明了它们参与BD易感性。我们还发现风险SNP与淋巴母细胞（P<0.005）和前额叶皮层（P<1.0 × 10−6）中CREB 1的表达密切相关。值得注意的是，群体遗传学分析表明，CREB 1在大陆人群之间的等位基因频率存在显着差异，而东亚人群中完全不存在风险等位基因。我们证明，CREB 1风险等位基因在欧洲人中的区域流行可能是由于自然选择作用于附近基因的遗传搭便车造成的。我们的研究结果表明，不同的人口历史，由于自然选择的区域人口可能会导致遗传异质性的易感性复杂的疾病，如BD，并解释不一致的检测这些疾病的遗传标记在不同的种族人群。
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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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
9.8
作者：
Cichon, Sven;Muehleisen, Thomas W.;Noethen, Markus M.
通讯作者：
Noethen, Markus M.
DOI：
10.1098/rspb.2007.0876
发表时间：
2007-11-22
影响因子：
4.7
作者：
Crespi, Bernard;Summers, Kyle;Dorus, Steve
通讯作者：
Dorus, Steve
影响因子：
30.8
作者：
Ferreira, Manuel A. R.;O'Donovan, Michael C.;Meng, Yan A.;Jones, Ian R.;Ruderfer, Douglas M.;Jones, Lisa;Fan, Jinbo;Kirov, George;Perlis, Roy H.;Green, Elaine K.;Smoller, Jordan W.;Grozeva, Detelina;Stone, Jennifer;Nikolov, Ivan;Chambert, Kimberly;Hamshere, Marian L.;Nimgaonkar, Vishwajit L.;Moskvina, Valentina;Thase, Michael E.;Caesar, Sian;Sachs, Gary S.;Franklin, Jennifer;Gordon-Smith, Katherine;Ardlie, Kristin G.;Gabriel, Stacey B.;Fraser, Christine;Blumenstiel, Brendan;Defelice, Matthew;Breen, Gerome;Gill, Michael;Morris, Derek W.;Elkin, Amanda;Muir, Walter J.;McGhee, Kevin A.;Williamson, Richard;MacIntyre, Donald J.;MacLean, Alan W.;Clair, David St;Robinson, Michelle;Van Beck, Margaret;Pereira, Ana C. P.;Kandaswamy, Radhika;McQuillin, Andrew;Collier, David A.;Bass, Nicholas J.;Young, Allan H.;Lawrence, Jacob;Ferrier, I. Nicol;Anjorin, Adebayo;Farmer, Anne;Curtis, David;Scolnick, Edward M.;McGuffin, Peter;Daly, Mark J.;Corvin, Aiden P.;Holmans, Peter A.;Blackwood, Douglas H.;Gurling, Hugh M.;Owen, Michael J.;Purcell, Shaun M.;Sklar, Pamela;Craddock, Nick
通讯作者：
Craddock, Nick