A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.
A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.
复制标题
DOI：
10.1371/journal.pone.0032091
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Welsh DK
中科院分区：
文献类型：
--
作者：
McCarthy MJ;Nievergelt CM;Kelsoe JR;Welsh DK
双相情感障碍（BD）的昼夜节律异常导致了对与双相情感障碍相关的昼夜节律“时钟基因”遗传异常的研究。然而，在全基因组关联研究（GWAS）中没有出现显著的时钟基因发现。至少有三个因素可以解释这种差异：复杂的特征是多基因的，生物钟的组织比以前认识到的更复杂，和/或双相障碍的遗传风险可能在多种疾病中共享。为了研究这些问题，我们从三个层面考虑了时钟基因网络：基本的“核心”时钟基因，上游生物钟调节因子和下游时钟控制基因。使用放宽的GWAS统计显著性阈值，我们确定了生物钟与对照组与双相障碍遗传关联的比率，以及四种与双相障碍具有共同临床特征和/或遗传风险的其他疾病（重度抑郁症、精神分裂症、注意力缺陷/多动症）。然后，我们将结果与一组锂响应基因进行了比较。与bd频谱疾病和锂反应性的关联在核心时钟基因中都有增强，但在上游时钟调节基因中没有。在普遍有节奏的生物钟控制基因中，与bd谱系疾病和锂反应性的关联也丰富，但在不那么普遍有节奏或无节奏的基因中则没有。我们的分析揭示了以前未被认识到的时钟基因与bd谱系疾病之间的关联，部分地调和了以前GWAS和候选基因研究的不一致结果。
Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian “clock genes” associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential “core” clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.
登录
查看更多内容
DOI：
10.1002/ajmg.b.30602
发表时间：
2008-04-05
影响因子：
2.8
作者：
Kissling, Christian;Retz, Wolfgang;Thome, Johannes
通讯作者：
Thome, Johannes
影响因子：
3.8
作者：
Bosetti, F;Seemann, R;Manickam, P
通讯作者：
Manickam, P
DOI：
10.1073/pnas.0811410106
发表时间：
2008-12-30
影响因子：
11.1
作者：
Hirota, Tsuyoshi;Lewis, Warren G.;Kay, Steve A.
通讯作者：
Kay, Steve A.
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
影响因子：
--
作者：
Kripke DF;Nievergelt CM;Joo E;Shekhtman T;Kelsoe JR
通讯作者：
Kelsoe JR