Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders.
Copy number variation meta-analysis reveals a novel duplication at 9p24 associated with multiple neurodevelopmental disorders.
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DOI：
10.1186/s13073-017-0494-1
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发表时间：
2017-11-30
期刊：
影响因子：
12.3
通讯作者：
Janssen-CHOP Neuropsychiatric Genomics Working Group
中科院分区：
文献类型：
--
作者：
Glessner JT;Li J;Wang D;March M;Lima L;Desai A;Hadley D;Kao C;Gur RE;Cohen N;Sleiman PMA;Li Q;Hakonarson H;Janssen-CHOP Neuropsychiatric Genomics Working Group
神经发育和神经精神障碍代表了广泛的异质但相互关联的疾病状况。这些疾病重叠的临床表现表明有共同的遗传病因。我们的目标是确定跨越五个神经精神疾病的频谱共享的结构变异。我们调查了5个队列的拷贝数变异（CNVs），包括精神分裂症（SCZ）、双相情感障碍（BD）、自闭症谱系障碍（ASD）、注意缺陷多动障碍（ADHD）和抑郁症，来自7849例病例和10,799例对照。基于全基因组SNP阵列的强度数据调用CNV，并分别比较每个疾病队列中病例和对照之间的CNV频率。通过基于基因的方法进行荟萃分析。采用定量PCR（qPCR）验证新的显著位点。在我们的荟萃分析中，两个含有外显子重叠的CNVs的基因达到了全基因组显著性阈值，缺失的Meta P值< 9.4 × 10−6，重复的meta P值<7.5 × 10−6。我们观察到不同队列的CNV风险位点之间存在显著重叠。此外，我们在所有队列中发现了DOCK 8/KANK 1重复的新的显著关联（Meta P值= 7.5 × 10−7），并进一步用qPCR验证了CNV区域。在对多种神经发育/精神疾病的CNV进行的第一次大规模荟萃分析中，我们发现了五种疾病共有的DOCK 8/KANK 1基因座结构变异的新的显著关联，表明这些临床上不同的神经发育疾病的共同病因。本文的在线版本（doi：10.1186/s13073-017-0494-1）包含补充材料，可供授权用户使用。
Neurodevelopmental and neuropsychiatric disorders represent a wide spectrum of heterogeneous yet inter-related disease conditions. The overlapping clinical presentations of these diseases suggest a shared genetic etiology. We aim to identify shared structural variants spanning the spectrum of five neuropsychiatric disorders. We investigated copy number variations (CNVs) in five cohorts, including schizophrenia (SCZ), bipolar disease (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and depression, from 7849 cases and 10,799 controls. CNVs were called based on intensity data from genome-wide SNP arrays and CNV frequency was compared between cases and controls in each disease cohort separately. Meta-analysis was performed via a gene-based approach. Quantitative PCR (qPCR) was employed to validate novel significant loci. In our meta-analysis, two genes containing CNVs with exonic overlap reached genome-wide significance threshold of meta P value < 9.4 × 10−6 for deletions and 7.5 × 10−6 for duplications. We observed significant overlap between risk CNV loci across cohorts. In addition, we identified novel significant associations of DOCK8/KANK1 duplications (meta P value = 7.5 × 10−7) across all cohorts, and further validated the CNV region with qPCR. In the first large scale meta-analysis of CNVs across multiple neurodevelopmental/psychiatric diseases, we uncovered novel significant associations of structural variants in the locus of DOCK8/KANK1 shared by five diseases, suggesting common etiology of these clinically distinct neurodevelopmental conditions. The online version of this article (doi:10.1186/s13073-017-0494-1) contains supplementary material, which is available to authorized users.
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影响因子：
1.1
作者：
Hassfurther, Ariane;Komini, Eleni;Leipoldt, Michael
通讯作者：
Leipoldt, Michael
DOI：
10.1002/ajmg.b.31063
发表时间：
2010-06-05
影响因子：
2.8
作者：
Ching, Michael S. L.;Shen, Yiping;Tan, Wen-Hann;Jeste, Shafali S.;Morrow, Eric M.;Chen, Xiaoli;Mukaddes, Nahit M.;Yoo, Seung-Yun;Hanson, Ellen;Hundley, Rachel;Austin, Christina;Becker, Ronald E.;Berry, Gerard T.;Driscoll, Katherine;Engle, Elizabeth C.;Friedman, Sandra;Gusella, James F.;Hisama, Fuki M.;Irons, Mira B.;Lafiosca, Tina;LeClair, Elaine;Miller, David T.;Neessen, Michael;Picker, Jonathan D.;Rappaport, Leonard;Rooney, Cynthia M.;Sarco, Dean P.;Stoler, Joan M.;Walsh, Christopher A.;Wolff, Robert R.;Zhang, Ting;Nasir, Ramzi H.;Wu, Bai-Lin
通讯作者：
Wu, Bai-Lin
影响因子：
30.8
作者：
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Nicol;Flickinger, Matthew;Fombonne, Eric;Foroud, Tatiana;Frank, Josef;Franke, Barbara;Fraser, Christine;Freedman, Robert;Freimer, Nelson B.;Freitag, Christine M.;Friedl, Marion;Frisen, Louise;Gallagher, Louise;Gejman, Pablo V.;Georgieva, Lyudmila;Gershon, Elliot S.;Geschwind, Daniel H.;Giegling, Ina;Gill, Michael;Gordon, Scott D.;Gordon-Smith, Katherine;Green, Elaine K.;Greenwood, Tiffany A.;Grice, Dorothy E.;Gross, Magdalena;Grozeva, Detelina;Guan, Weihua;Gurling, Hugh;De Haan, Lieuwe;Haines, Jonathan L.;Hakonarson, Hakon;Hallmayer, Joachim;Hamilton, Steven P.;Hamshere, Marian L.;Hansen, Thomas F.;Hartmann, Annette M.;Hautzinger, Martin;Heath, Andrew C.;Henders, Anjali K.;Herms, Stefan;Hickie, Ian B.;Hipolito, Maria;Hoefels, Susanne;Holmans, Peter A.;Holsboer, Florian;Hoogendijk, Witte J.;Hottenga, Jouke-Jan;Hultman, Christina M.;Hus, Vanessa;Ingason, Andres;Ising, Marcus;Jamain, Stephane;Jones, Edward G.;Jones, Ian;Jones, Lisa;Tzeng, Jung-Ying;Kaehler, Anna K.;Kahn, Rene S.;Kandaswamy, Radhika;Keller, Matthew C.;Kennedy, James L.;Kenny, Elaine;Kent, Lindsey;Kim, Yunjung;Kirov, George K.;Klauck, Sabine M.;Klei, Lambertus;Knowles, James A.;Kohli, Martin A.;Koller, Daniel L.;Konte, Bettina;Korszun, Ania;Krabbendam, Lydia;Krasucki, Robert;Kuntsi, Jonna;Kwan, Phoenix;Landen, Mikael;Langstrom, Niklas;Lathrop, Mark;Lawrence, Jacob;Lawson, William B.;Leboyer, Marion;Ledbetter, David H.;Lee, Phil H.;Lencz, Todd;Lesch, Klaus-Peter;Levinson, Douglas F.;Lewis, Cathryn M.;Li, Jun;Lichtenstein, Paul;Lieberman, Jeffrey A.;Lin, Dan-Yu;Linszen, Don H.;Liu, Chunyu;Lohoff, Falk W.;Loo, Sandra K.;Lord, Catherine;Lowe, Jennifer K.;Lucae, Susanne;MacIntyre, Donald J.;Madden, Pamela A. 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通讯作者：
Wray, Naomi R.
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
14.9
作者：
Glessner JT;Li J;Hakonarson H
通讯作者：
Hakonarson H