Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.
Epistatic interaction of genetic depression risk variants in the human subgenual cingulate cortex during memory encoding.
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DOI：
10.1038/tp.2014.10
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发表时间：
2014-03-18
影响因子：
6.8
通讯作者：
Walter H
中科院分区：
文献类型：
--
作者：
Schott BH;Assmann A;Schmierer P;Soch J;Erk S;Garbusow M;Mohnke S;Pöhland L;Romanczuk-Seiferth N;Barman A;Wüstenberg T;Haddad L;Grimm O;Witt S;Richter S;Klein M;Schütze H;Mühleisen TW;Cichon S;Rietschel M;Noethen MM;Tost H;Gundelfinger ED;Düzel E;Heinz A;Meyer-Lindenberg A;Seidenbecher CI;Walter H
最近的全基因组关联研究指出，编码神经元钙通道CaV1.2(CACNA1C；rs1006737)和突触前活动区蛋白Piccolo(PCLO；rs2522833)的基因的单核苷酸多态(SNPs)是情感性障碍，特别是重度抑郁症的危险因素。以前对抑郁症相关内表型的神经成像研究已经强调了扣带回皮质(CG25)在消极情绪和抑郁心理病理中的作用。在这里，我们旨在评估最近相关的PCLO和CACNA1C抑郁风险等位基因如何共同影响作为临床健康人的中间表型的记忆相关CG25活性。为了研究rs1006737和rs2522833对CG25反应的联合作用，我们在三个独立的队列(N=79,300,113)中进行了三种情景记忆形成的功能磁共振成像研究。CG25中PCLO和CACNA1C风险等位基因在记忆编码过程中存在上位性交互作用，与只有一个风险等位基因的携带者相比，无风险等位基因携带者和两种风险等位基因携带者在编码过程中CG25的激活程度都较高。此外，PCLO风险等位基因携带者表现出较低的记忆能力和与编码相关的海马区激活减少。综上所述，我们的结果指出了CG25中PCLO和CACNA1C风险变量的区域特异性上位性效应，可能与情景记忆有关。我们的数据进一步表明，SNP水平上的遗传风险因素不一定具有相加效应，但可能表现出复杂的相互作用。这种上位性相互作用可能导致复杂表型的“缺失遗传性”。
Recent genome-wide association studies have pointed to single-nucleotide polymorphisms (SNPs) in genes encoding the neuronal calcium channel CaV1.2 (CACNA1C; rs1006737) and the presynaptic active zone protein Piccolo (PCLO; rs2522833) as risk factors for affective disorders, particularly major depression. Previous neuroimaging studies of depression-related endophenotypes have highlighted the role of the subgenual cingulate cortex (CG25) in negative mood and depressive psychopathology. Here, we aimed to assess how recently associated PCLO and CACNA1C depression risk alleles jointly affect memory-related CG25 activity as an intermediate phenotype in clinically healthy humans. To investigate the combined effects of rs1006737 and rs2522833 on the CG25 response, we conducted three functional magnetic resonance imaging studies of episodic memory formation in three independent cohorts (N=79, 300, 113). An epistatic interaction of PCLO and CACNA1C risk alleles in CG25 during memory encoding was observed in all groups, with carriers of no risk allele and of both risk alleles showing higher CG25 activation during encoding when compared with carriers of only one risk allele. Moreover, PCLO risk allele carriers showed lower memory performance and reduced encoding-related hippocampal activation. In summary, our results point to region-specific epistatic effects of PCLO and CACNA1C risk variants in CG25, potentially related to episodic memory. Our data further suggest that genetic risk factors on the SNP level do not necessarily have additive effects but may show complex interactions. Such epistatic interactions might contribute to the ‘missing heritability' of complex phenotypes.
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影响因子：
3.5
作者：
Hek, Karin;Mulder, Cornelis L.;Tiemeier, Henning
通讯作者：
Tiemeier, Henning
影响因子：
9.8
作者：
Cichon, Sven;Muehleisen, Thomas W.;Noethen, Markus M.
通讯作者：
Noethen, Markus M.
影响因子：
10.6
作者：
Greicius, Michael D.;Flores, Benjamin H.;Schatzberg, Alan F.
通讯作者：
Schatzberg, Alan F.
DOI：
10.1176/appi.ajp.2010.10040484
发表时间：
2010-12
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Feyder M;Karlsson RM;Mathur P;Lyman M;Bock R;Momenan R;Munasinghe J;Scattoni ML;Ihne J;Camp M;Graybeal C;Strathdee D;Begg A;Alvarez VA;Kirsch P;Rietschel M;Cichon S;Walter H;Meyer-Lindenberg A;Grant SG;Holmes A
通讯作者：
Holmes 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