Rare chromosomal deletions and duplications increase risk of schizophrenia.
Rare chromosomal deletions and duplications increase risk of schizophrenia.
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DOI：
10.1038/nature07239
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发表时间：
2008-09-11
期刊：
影响因子：
64.8
通讯作者：
Sklar, P.
中科院分区：
文献类型：
--
作者：
Stone, Jennifer L.;O'Donovan, Michael C.;Gurling, Hugh;Kirov, George K.;Blackwood, Douglas H. R.;Corvin, Aiden;Craddock, Nick J.;Gill, Michael;Hultman, Christina M.;Lichtenstein, Paul;McQuillin, Andrew;Pato, Carlos N.;Ruderfer, Douglas M.;Owen, Michael J.;St Clair, David;Sullivan, Patrick F.;Sklar, Pamela;Purcell, Shaun M.;Scolnick, E. M.;Holmans, P. A.;Georgieva, L.;Nikolov, I.;Norton, N.;Williams, H.;Williams, N. M.;Toncheva, D.;Milanova, V.;Thelander, E. F.;Morris, D. W.;O'Dushlaine, C. T.;Kenny, E.;Waddington, J. L.;Choudhury, K.;Datta, S.;Pimm, J.;Thirumalai, S.;Puri, V.;Krasucki, R.;Lawrence, J.;Quested, D.;Bass, N.;Curtis, D.;Crombie, C.;Fraser, G.;Kwan, S. L.;Muir, W. J.;McGhee, K. A.;Pickard, B.;Malloy, P.;Maclean, A. W.;Van Beck, M.;Visscher, P. M.;Macgregor, S.;Pato, M. T.;Medeiros, H.;Middleton, F.;Carvalho, C.;Morley, C.;Fanous, A.;Conti, D.;Knowles, J. A.;Ferreira, C. P.;Azevedo, M. H.;McCarroll, S. A.;Gates, C.;Daly, M. J.;Sklar, P.
精神分裂症是一种严重的精神障碍，以幻觉、妄想、认知缺陷和冷漠为特征，遗传率估计为73-90%（参考文献1）。遗传模式是复杂的，涉及的遗传变异的数量和类型尚不清楚。拷贝数变异（CNV）已在精神分裂症患者个体2 -7和神经发育障碍8 -11中被确定，但尚未进行大规模的全基因组调查。在这里，我们报告了一项使用高密度微阵列对3，391名精神分裂症患者和3，181名祖先匹配的对照进行的罕见CNV的全基因组调查。对于在少于1%的样本中观察到的CNV，长度超过100个碱基，与对照组相比，精神分裂症患者的总负担增加了1.15倍。这种效应对于罕见的、单次出现的CNV和那些涉及基因的CNV比那些不涉及基因的CNV更明显。正如预期的那样，在对腭心面综合征至关重要的区域内发现了缺失，其中包括30%的患者的精神病症状12。与精神分裂症的关联也被发现在染色体15 q13的大缺失。3和1 q21。1.这些关联以前没有被报道过，在全基因组校正后它们仍然显着。我们的研究结果为精神分裂症发病机制的模型提供了强有力的支持，该模型包括多个罕见结构变异的影响，包括全基因组和特定基因座。国际精神分裂症联盟的成立是为了促进在确定精神分裂症的遗传原因方面取得快速进展。该联盟由来自阿伯丁大学、卡迪夫大学、爱丁堡大学、卡罗林斯卡学院、马萨诸塞州总医院、北卡罗来纳大学教堂山分校、昆士兰州医学研究所、南加州大学、哈佛和麻省理工学院布罗德研究所斯坦利精神病学研究中心的研究人员组成，Trinity College都柏林和University College伦敦。我们使用AffysseTM全基因组人类SNP 5.0和6.0阵列调查了欧洲精神分裂症病例和祖先匹配对照的单核苷酸多态性（SNP）和CNV（表1和补充信息）13。基于全基因组SNP数据，在每个位点内没有主要群体分层的证据14（数据未显示）。基于隐马尔可夫模型，使用来自SNP和CNV探针的强度数据来鉴定常染色体缺失和重复15。这项研究的重点是罕见的，但高度渗透的结构变异精神分裂症，以下的经典医学遗传学方法的自然延伸。常见的CNV可以用不同的算法更好地识别，并且可以更好地分别测试关联性13，15。考虑到CNV存在于少于我们总样品的1%中，有6，753个大于100 kb的RNA酶通过了样品和CNV质量过滤（参见补充材料
Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73–90%(ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia2–7 and also in neurodevelopmental disorders8–11, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients12. Associations with schizophrenia were also found for large deletions on chromosome 15q13. 3 and 1q21. 1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci. The International Schizophrenia Consortium was established to promote rapid progress towards the identification of genetic causes underlying schizophrenia. The consortium is composed of investigators from the University of Aberdeen, Cardiff University, the University of Edinburgh, Karolinska Institutet, Massachusetts General Hospital, the University of North Carolina-Chapel Hill, the Queensland Institute of Medical Research, the University of Southern California, the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Trinity College Dublin and University College London.We surveyed single nucleotide polymorphisms (SNPs) and CNVs using the Affymetrix Genome-Wide Human SNP 5.0 and 6.0 arrays in European cases of schizophrenia and in ancestrally matched controls (Table 1 and Supplementary Information) 13. On the basis of the genome-wide SNP data there was no evidence of major population stratification within each site14 (data not shown). Intensity data from both SNP and CNV probes were used to identify autosomal deletions and duplications, based on a hidden Markov model15. This study focused on rare but highly penetrant structural variation in schizophrenia, following a natural extension of the classical medical genetic approach. Common CNVs are better identified with different algorithms and are better tested for association separately13, 15. Considering CNVs that were present in less than 1% of our total sample, there were 6,753 larger than 100 kilobases (kb) that passed sample and CNV quality filtering (see Supplementary
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影响因子：
30.8
作者：
Sharp, Andrew J.;Mefford, Heather C.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
DOI：
10.1002/ajmg.b.30306
发表时间：
2006-09-05
影响因子：
2.8
作者：
Flomen, Rachel H.;Collier, David A.;Makoff, Andrew J.
通讯作者：
Makoff, Andrew J.
影响因子：
158.5
作者：
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通讯作者：
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影响因子：
9.8
作者：
Gurling, HMD;Kalsi, G;Curtis, D
通讯作者：
Curtis, D
影响因子：
3.5
作者：
Shaikh, TH;Kurahashi, H;Emanuel, BS
通讯作者：
Emanuel, BS