Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).
Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).
复制标题
DOI：
10.1038/mp.2013.166
复制
发表时间：
2014-02
影响因子：
11
通讯作者：
Malhotra, A. K.
中科院分区：
文献类型：
--
作者：
Lencz, T.;Knowles, E.;Davies, G.;Guha, S.;Liewald, D. C.;Starr, J. M.;Djurovic, S.;Melle, I.;Sundet, K.;Christoforou, A.;Reinvang, I.;Mukherjee, S.;DeRosse, Pamela;Lundervold, A.;Steen, V. M.;John, M.;Espeseth, T.;Raikkonen, K.;Widen, E.;Palotie, A.;Eriksson, J. G.;Giegling, I.;Konte, B.;Ikeda, M.;Roussos, P.;Giakoumaki, S.;Burdick, K. E.;Payton, A.;Ollier, W.;Horan, M.;Donohoe, G.;Morris, D.;Corvin, A.;Gill, M.;Pendleton, N.;Iwata, N.;Darvasi, A.;Bitsios, P.;Rujescu, D.;Lahti, J.;Hellard, S. L.;Keller, M. C.;Andreassen, O. A.;Deary, I. J.;Glahn, D. C.;Malhotra, A. K.
长期以来，人们一直认为，认知能力的普遍缺陷是精神分裂症的核心组成部分，在完全发病之前就很明显，而且不依赖于药物。精神分裂症患者的一级亲属存在认知缺陷，这表明精神分裂症的风险和认知表型之间存在遗传重叠的可能性；然而，直到最近，还缺乏测试这种重叠的分子遗传学方法。在过去的几年里，对精神分裂症的大规模全基因组关联研究(Gwas)表明，这种疾病的遗传性中有相当大一部分是由许多影响极小的常见SNP组成的多基因成分解释的。在具有一般认知能力的GWA中也报道了类似的结果。本研究的主要目的是为经典的内表型假说提供第一个分子遗传学检验，该假说认为与认知能力降低相关的等位基因也应该用于增加患精神分裂症的风险。我们通过对4个精神分裂症病例对照队列进行大规模认知GWASMeta分析(来自9个非临床队列的约5000名个体)的多基因SNP得分来检验内表型假说。正如预测的那样，与对照组相比，患者的认知多基因得分显著降低。同时，精神分裂症的多基因风险分数与一般认知能力较低有关。此外，使用我们的大型认知元分析数据集，我们确定了几个以前与精神分裂症易感性密切相关的SNP的名义上显著的认知关联。结果为精神分裂症和一般认知能力之间的遗传重叠提供了分子证实，并可能为精神分裂症的病理生理学提供更多的见解。
It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia, evident prior to full illness onset and independent of medication. The possibility of genetic overlap between risk for schizophrenia and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with schizophrenia; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of schizophrenia have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common SNPs of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for schizophrenia. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from 9 non-clinical cohorts comprising the COGENT consortium) to four schizophrenia case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for schizophrenia were associated with lower general cognitive ability. Additionally, using our large cognitive meta-analytic dataset, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with schizophrenia susceptibility. Results provide molecular confirmation of the genetic overlap between schizophrenia and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.
登录
查看更多内容
影响因子：
25.8
作者：
Guha, Saurav;Rees, Elliott;Darvasi, Ariel;Ivanov, Dobril;Ikeda, Masashi;Bergen, Sarah E.;Magnusson, Patrik K.;Cormican, Paul;Morris, Derek;Gill, Michael;Cichon, Sven;Rosenfeld, Jeffrey A.;Lee, Annette;Gregersen, Peter K.;Kane, John M.;Malhotra, Anil K.;Rietschel, Marcella;Noethen, Markus M.;Degenhardt, Franziska;Priebe, Lutz;Breuer, Rene;Strohmaier, Jana;Ruderfer, Douglas M.;Moran, Jennifer L.;Chambert, Kimberly D.;Sanders, Alan R.;Shi, Jianxin;Kendler, Kenneth;Riley, Brien;O'Neill, Tony;Walsh, Dermot;Malhotra, Dheeraj;Corvin, Aiden;Purcell, Shaun;Sklar, Pamela;Iwata, Nakao;Hultman, Christina M.;Sullivan, Patrick F.;Sebat, Jonathan;McCarthy, Shane;Gejman, Pablo V.;Levinson, Douglas F.;Owen, Michael J.;O'Donovan, Michael C.;Lencz, Todd;Kirov, George
通讯作者：
Kirov, George
影响因子：
19.9
作者：
Bilder, Robert M.;Howe, Andrew;Novak, Nic;Sabb, Fred W.;Parker, D. Stott
通讯作者：
Parker, D. Stott
影响因子：
9.8
作者：
Andreassen, Ole A.;Djurovic, Srdjan;Dale, Anders M.
通讯作者：
Dale, Anders M.
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.
影响因子：
3
作者：
Johnson, W;Bouchard, TJ;Gottesman, II
通讯作者：
Gottesman, II