The discovery of integrated gene networks for autism and related disorders.
The discovery of integrated gene networks for autism and related disorders.
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DOI：
10.1101/gr.178855.114
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发表时间：
2015-01
期刊：
影响因子：
7
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Hormozdiari F;Penn O;Borenstein E;Eichler EE
尽管神经发育疾病具有相当大的遗传异质性，但有令人信服的证据表明，许多疾病基因将映射到数量少得多的生物子网络。我们开发了一种名为MAGI（将受影响的基因合并到集成网络中）的计算方法，该方法同时整合了大脑发育过程中的蛋白质-蛋白质相互作用和RNA-seq表达谱，以发现先证者中富含从头突变的“模块”。我们将这种方法应用于最近1116例自闭症和智力残疾患者的外显子组测序，发现了两个不同的模块，其性质和相关表型不同。第一个模块由与Wnt、Notch、SWI/SNF和NCOR复合物相关的80个基因组成，并且在胚胎发育早期（受孕后8-16周[pcw]）显示出最高表达。第二个模块由24个与突触功能相关的基因组成，包括长时程增强和出生后表达水平较高的钙信号。在这些模块中具有新生突变的患者与在这些模块之外具有新生突变的先证者相比，智力受损更显著，并且携带更严重的错义突变。我们使用我们的方法来定义与高功能自闭症相关的网络子集，以及智商方面的更大严重性。最后，我们将MAGI独立应用于癫痫和精神分裂症外显子组测序队列，发现这些模块有显著的重叠和扩展，这表明似乎不同的人类疾病共有一套核心的综合神经发育网络。
Despite considerable genetic heterogeneity underlying neurodevelopmental diseases, there is compelling evidence that many disease genes will map to a much smaller number of biological subnetworks. We developed a computational method, termed MAGI (merging affected genes into integrated networks), that simultaneously integrates protein–protein interactions and RNA-seq expression profiles during brain development to discover “modules” enriched for de novo mutations in probands. We applied this method to recent exome sequencing of 1116 patients with autism and intellectual disability, discovering two distinct modules that differ in their properties and associated phenotypes. The first module consists of 80 genes associated with Wnt, Notch, SWI/SNF, and NCOR complexes and shows the highest expression early during embryonic development (8–16 post-conception weeks [pcw]). The second module consists of 24 genes associated with synaptic function, including long-term potentiation and calcium signaling with higher levels of postnatal expression. Patients with de novo mutations in these modules are more significantly intellectually impaired and carry more severe missense mutations when compared to probands with de novo mutations outside of these modules. We used our approach to define subsets of the network associated with higher functioning autism as well as greater severity with respect to IQ. Finally, we applied MAGI independently to epilepsy and schizophrenia exome sequencing cohorts and found significant overlap as well as expansion of these modules, suggesting a core set of integrated neurodevelopmental networks common to seemingly diverse human diseases.
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
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Wigler M
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Lin CC;Hsiang JT;Wu CY;Oyang YJ;Juan HF;Huang HC
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Huang HC
影响因子：
10.6
作者：
Amiet, Claire;Gourfinkel-An, Isabelle;Cohen, David
通讯作者：
Cohen, David
影响因子：
64.8
作者：
Kong A;Frigge ML;Masson G;Besenbacher S;Sulem P;Magnusson G;Gudjonsson SA;Sigurdsson A;Jonasdottir A;Jonasdottir A;Wong WS;Sigurdsson G;Walters GB;Steinberg S;Helgason H;Thorleifsson G;Gudbjartsson DF;Helgason A;Magnusson OT;Thorsteinsdottir U;Stefansson K
通讯作者：
Stefansson K
影响因子：
12.3
作者：
Hart GT;Ramani AK;Marcotte EM
通讯作者：
Marcotte EM