Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.
Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.
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DOI：
10.1176/appi.ajp.2017.16121417
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发表时间：
2017-11-01
期刊：
影响因子：
--
通讯作者：
International 22q11.2DS Brain and Behavior Consortium
中科院分区：
文献类型：
--
作者：
Bassett AS;Lowther C;Merico D;Costain G;Chow EWC;van Amelsvoort T;McDonald-McGinn D;Gur RE;Swillen A;Van den Bree M;Murphy K;Gothelf D;Bearden CE;Eliez S;Kates W;Philip N;Sashi V;Campbell L;Vorstman J;Cubells J;Repetto GM;Simon T;Boot E;Heung T;Evers R;Vingerhoets C;van Duin E;Zackai E;Vergaelen E;Devriendt K;Vermeesch JR;Owen M;Murphy C;Michaelovosky E;Kushan L;Schneider M;Fremont W;Busa T;Hooper S;McCabe K;Duijff S;Isaev K;Pellecchia G;Wei J;Gazzellone MJ;Scherer SW;Emanuel BS;Guo T;Morrow BE;Marshall CR;International 22q11.2DS Brain and Behavior Consortium
22q11.2 缺失综合征 (22q11.2DS) 与患精神分裂症的风险增加 20 倍以上相关。本研究的目的是确定可能导致精神分裂症表达的其他遗传因素（即“第二次打击”）。通过一个国际联盟，我们从 329 名患有 22q11.2DS 的精神病学表型受试者中获取了 DNA 样本。使用高分辨率微阵列平台和已建立的评估拷贝数变异 (CNV) 的方法，我们比较了两组之间 22q11.2 缺失区域之外的罕见常染色体 CNV 的全基因组负担：有精神障碍和年龄≥25 岁、无精神障碍。我们评估了罕见 CNV 重叠的基因在与精神分裂症相关的功能通路中是否存在过度表达。与一个或多个蛋白质编码基因重叠的罕见 CNV 揭示了显着的组间差异。对于罕见的外显子重复，测试的 19 个基因组中有 6 个在精神分裂症组中富集；与异常神经系统表型相关的基因在逐步逻辑回归模型中仍然显着（p = 0.00062），并且在连接分析中显示出与 22q11.2 缺失区域基因的显着相互作用。对于罕见的外显子缺失，精神分裂症组平均有更多的基因重叠（p=0.0058）。其他罕见的 CNV 涉及已知（例如 GRM7、15q13.3、16p12.2）和新的精神分裂症风险基因和位点。结果表明，22q11.2 缺失区域之外的其他罕见 CNV 重叠基因会导致 22q11.2DS 中的精神分裂症风险，支持精神分裂症的多基因假说。这些发现对于理解精神疾病的表达具有重要意义，并预示着全基因组测序对于理解精神分裂症整体基因组结构的重要性。
22q11.2 deletion syndrome (22q11.2DS) is associated with a >20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., “second hits”) that may contribute to schizophrenia expression. Through an international consortium we obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), we compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: with and, at age ≥25 years, without a psychotic disorder. We assessed whether genes overlapped by rare CNVs were over-represented in functional pathways relevant to schizophrenia. Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene-sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a step-wise logistic regression model (p=0.00062) and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had on average more genes overlapped (p=0.0058). The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci. The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness, and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.
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影响因子：
14.9
作者：
Kozomara A;Griffiths-Jones S
通讯作者：
Griffiths-Jones S
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
DOI：
10.1038/ejhg.2015.218
发表时间：
2016-06
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Ambalavanan A;Girard SL;Ahn K;Zhou S;Dionne-Laporte A;Spiegelman D;Bourassa CV;Gauthier J;Hamdan FF;Xiong L;Dion PA;Joober R;Rapoport J;Rouleau GA
通讯作者：
Rouleau GA
影响因子：
9.8
作者：
Miller, David T.;Adam, Margaret P.;Ledbetter, David H.
通讯作者：
Ledbetter, David H.
影响因子：
10.6
作者：
Kirov, George;Rees, Elliott;Walters, James T. R.;Escott-Price, Valentina;Georgieva, Lyudmila;Richards, Alexander L.;Chambert, Kimberly D.;Davies, Gerwyn;Legge, Sophie E.;Moran, Jennifer L.;McCarroll, Steven A.;O'Donovan, Michael C.;Owen, Michael J.
通讯作者：
Owen, Michael J.