Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders.
Integrated gene analyses of de novo variants from 46,612 trios with autism and developmental disorders.
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DOI：
10.1073/pnas.2203491119
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发表时间：
2022-11-15
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
神经发育障碍（NDD）是一组异质性障碍，包括自闭症谱系障碍（ASD）和发育障碍（DD）。我们使用三种模型从15，560例ASD和31，052例DD亲子三人组中独立地搜索了富集从头变异的基因，并将其组合为更广泛的NDD组。我们鉴定了615个候选者（错误发现率[FDR] < 0.05），其由一个或多个模型支持，其中138个在所有模型中达到外显子组范围的显著性（P < 3.64e-7）。NDD基因分为五个功能网络，在发育中的大脑中具有不同的单细胞表达模式。我们没有发现ASD特异性基因，虽然18个基因是专门为DD富集，我们确定了53个基因的突变偏见，以及10个基因的性别偏见。这种大规模的综合分析为未来的研究提供了候选人。大多数遗传学研究认为自闭症谱系障碍（ASD）和发育障碍（DD）分开，尽管压倒性的共病和共同的遗传病因。在这里，我们分析了来自15，560名ASD（6，557名来自SPARK）和31，052名DD三人组的从头变异（DNV），并使用三种模型将其合并为更广泛的神经发育障碍（NDD）。我们鉴定了615个NDD候选基因（假发现率[FDR] < 0.05），其由≥1个模型支持，其中138个在所有模型中达到Bonferroni外显子组范围显著性（P < 3.64e-7）。基于单细胞核转录组学数据，这些基因分为五个与不同脑发育谱系相关的功能网络。我们没有发现ASD特异性基因的证据，相反，18个基因显着丰富的DD。有53个基因显示突变偏倚，包括错义（n = 41）或截短（n = 12）DNV的富集。我们还发现了10个具有男性或女性偏好富集证据的基因，包括4个具有显著女性负担的X染色体基因（DDX 3X，MECP 2，WDR 45和HDAC 8）。这种大规模的综合分析确定了NDD基因的候选者和功能子集。
Neurodevelopmental disorders (NDDs) are a group of heterogeneous disorders encompassing both autism spectrum disorder (ASD) and developmental disorder (DD). We searched for genes enriched for de novo variants from 15,560 ASD and 31,052 DD parent–child trios independently and combined as a broader NDD group using three models. We identify 615 candidates (false discovery rate [FDR] < 0.05) supported by one or more model, 138 of which reach exome-wide significance (P < 3.64e–7) in all models. NDD genes group into five functional networks with distinct patterns of single-cell expression in the developing brain. We find no ASD-specific genes, although 18 genes are specifically enriched for DD, and we identify 53 genes with mutational bias as well as 10 genes with sex bias. This large-scale integrative analysis provides candidates for future investigation. Most genetic studies consider autism spectrum disorder (ASD) and developmental disorder (DD) separately despite overwhelming comorbidity and shared genetic etiology. Here, we analyzed de novo variants (DNVs) from 15,560 ASD (6,557 from SPARK) and 31,052 DD trios independently and also combined as broader neurodevelopmental disorders (NDDs) using three models. We identify 615 NDD candidate genes (false discovery rate [FDR] < 0.05) supported by ≥1 models, including 138 reaching Bonferroni exome-wide significance (P < 3.64e–7) in all models. The genes group into five functional networks associating with different brain developmental lineages based on single-cell nuclei transcriptomic data. We find no evidence for ASD-specific genes in contrast to 18 genes significantly enriched for DD. There are 53 genes that show mutational bias, including enrichments for missense (n = 41) or truncating (n = 12) DNVs. We also find 10 genes with evidence of male- or female-bias enrichment, including 4 X chromosome genes with significant female burden (DDX3X, MECP2, WDR45, and HDAC8). This large-scale integrative analysis identifies candidates and functional subsets of NDD genes.
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影响因子：
20.8
作者：
Lyall K;Croen L;Daniels J;Fallin MD;Ladd-Acosta C;Lee BK;Park BY;Snyder NW;Schendel D;Volk H;Windham GC;Newschaffer C
通讯作者：
Newschaffer C
影响因子：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
DOI：
10.1261/rna.053447.115
发表时间：
2016-01
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Kini HK;Silverman IM;Ji X;Gregory BD;Liebhaber SA
通讯作者：
Liebhaber SA
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
5.3
作者：
Snijders Blok L;Hiatt SM;Bowling KM;Prokop JW;Engel KL;Cochran JN;Bebin EM;Bijlsma EK;Ruivenkamp CAL;Terhal P;Simon MEH;Smith R;Hurst JA;DDD study;McLaughlin H;Person R;Crunk A;Wangler MF;Streff H;Symonds JD;Zuberi SM;Elliott KS;Sanders VR;Masunga A;Hopkin RJ;Dubbs HA;Ortiz-Gonzalez XR;Pfundt R;Brunner HG;Fisher SE;Kleefstra T;Cooper GM
通讯作者：
Cooper GM