De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.
De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.
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DOI：
10.1038/mp.2011.154
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发表时间：
2012-02
影响因子：
11
通讯作者：
Owen, M. J.
中科院分区：
文献类型：
--
作者：
Kirov, G.;Pocklington, A. J.;Holmans, P.;Ivanov, D.;Ikeda, M.;Ruderfer, D.;Moran, J.;Chambert, K.;Toncheva, D.;Georgieva, L.;Grozeva, D.;Fjodorova, M.;Wollerton, R.;Rees, E.;Nikolov, I.;van de Lagemaat, L. N.;Bayes, A.;Fernandez, E.;Olason, P. I.;Boettcher, Y.;Komiyama, N. H.;Collins, M. O.;Choudhary, J.;Stefansson, K.;Stefansson, H.;Grant, S. G. N.;Purcell, S.;Sklar, P.;O'Donovan, M. C.;Owen, M. J.
已知少数罕见的复发性基因组拷贝数变异（CNVs）会显著增加精神分裂症的易感性。由于这些CNV导致精神分裂症和其他神经发育表型患者的生育力较低，因此对风险有较大影响的CNV可能会通过自然选择迅速从人群中去除。因此，这样的CNV必须经常作为复发性从头突变发生。在662例精神分裂症先证者-父母三人组的样本中，我们发现罕见的新生CNV突变在病例中（5.1%的病例，5.5%的家族史阴性）明显更频繁，而在2623例对照中为2.2%，证实了新生CNV参与精神分裂症的发病机制。8个新的CNVs发生在4个已知的精神分裂症位点（3q 29，15q11.2，15q13.3和16p11.2）。在其他基因组疾病中也观察到已知致病意义的从头CNV，包括1q21.1上TAR（血小板减少症缺失半径）区域的缺失和7q11.23上WBS（Williams-Beuren综合征）区域的重复。多个从头跨越的基因编码的DLG（大碟）家族的膜相关鸟苷酸激酶（MAGUKs）的成员，是突触后密度（PSD）的组成部分。两个de novos也影响了EHMT 1，一种已知直接调节DLG家族成员的组蛋白甲基转移酶。使用系统生物学方法并合并新的CNV和蛋白质组学数据集，突触蛋白复合物的系统分析表明，与对照CNV相比，新生病例的PSD蛋白质组显著富集（P=1.72 × 10−6）。这在很大程度上可以通过富集N-甲基-D-天冬氨酸受体（NMDAR）（P=4.24 × 10−6）和神经元活性调节的细胞因子相关蛋白（ARC）（P=3.78 × 10−8）突触后信号复合物的成员来解释。在对18492例受试者（7907例病例和10585例对照）的分析中，病例CNV富集了NMDAR复合体的成员（P=0.0015），但没有ARC（P=0.14）。我们的数据表明，缺陷NMDAR突触后信号传导，并可能，ARC复合物，这是已知的重要的突触可塑性和认知，在精神分裂症的发病机制中发挥了重要作用。
A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband–parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams–Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10−6). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10−6) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10−8) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.
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影响因子：
11
作者：
通讯作者：
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影响因子：
30.8
作者：
McCarthy, Shane E.;Makarov, Vladimir;Kirov, George;Addington, Anjene M.;McClellan, Jon;Yoon, Seungtai;Perkins, Diana O.;Dickel, Diane E.;Kusenda, Mary;Krastoshevsky, Olga;Krause, Verena;Kumar, Ravinesh A.;Grozeva, Detelina;Malhotra, Dheeraj;Walsh, Tom;Zackai, Elaine H.;Kaplan, Paige;Ganesh, Jaya;Krantz, Ian D.;Spinner, Nancy B.;Roccanova, Patricia;Bhandari, Abhishek;Pavon, Kevin;Lakshmi, B.;Leotta, Anthony;Kendall, Jude;Lee, Yoon-ha;Vacic, Vladimir;Gary, Sydney;Iakoucheva, Lilia M.;Crow, Timothy J.;Christian, Susan L.;Lieberman, Jeffrey A.;Stroup, T. Scott;Lehtimaki, Terho;Puura, Kaija;Haldeman-Englert, Chad;Pearl, Justin;Goodell, Meredith;Willour, Virginia L.;DeRosse, Pamela;Steele, Jo;Kassem, Layla;Wolff, Jessica;Chitkara, Nisha;McMahon, Francis J.;Malhotra, Anil K.;Potash, James B.;Schulze, Thomas G.;Noethen, Markus M.;Cichon, Sven;Rietschel, Marcella;Leibenluft, Ellen;Kustanovich, Vlad;Lajonchere, Clara M.;Sutcliffe, James S.;Skuse, David;Gill, Michael;Gallagher, Louise;Mendell, Nancy R.;Craddock, Nick;Owen, Michael J.;O'Donovan, Michael C.;Shaikh, Tamim H.;Susser, Ezra;DeLisi, Lynn E.;Sullivan, Patrick F.;Deutsch, Curtis K.;Rapoport, Judith;Levy, Deborah L.;King, Mary-Claire;Sebat, Jonathan
通讯作者：
Sebat, Jonathan
影响因子：
9.8
作者：
Klopocki, Eva;Schulze, Harald;Mundlos, Stefan
通讯作者：
Mundlos, Stefan
影响因子：
30.8
作者：
Cooper, Gregory M.;Coe, Bradley P.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
9.8
作者：
Moreno-De-Luca, Daniel;Mulle, Jennifer G.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.