Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations.
Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations.
复制标题
DOI：
10.1016/j.xhgg.2022.100166
复制
发表时间：
2023-01-12
期刊：
影响因子：
--
通讯作者：
Ludwig, Kerstin U.
中科院分区：
文献类型：
--
作者：
Zieger, Hanna K.;Weinhold, Leonie;Schmidt, Axel;Holtgrewe, Manuel;Juranek, Stefan A.;Siewert, Anna;Scheer, Annika B.;Thieme, Frederic;Mangold, Elisabeth;Ishorst, Nina;Brand, Fabian U.;Welzenbach, Julia;Beule, Dieter;Paeschke, Katrin;Krawitz, Peter M.;Ludwig, Kerstin U.
非综合征性唇裂伴/不伴腭裂（nsCL/P）是一种高度遗传性面部疾病。迄今为止，对非编码区罕见变异对nsCL/P病因的贡献的系统调查很少。在这里，我们重新分析了211例欧洲nsCL/P病例-亲本三人组的现有全基因组序列（WGS）数据，并在nsCL/P病例中发现了13,522个新生突变（dnm），其中13,055个突变映射到非编码区。我们将这些数据与来自参考队列的dnm、先前全基因组关联研究（GWASs）的结果以及与胚胎面部发育相关的功能和表观遗传数据集进行整合。在两个GWAS风险位点（4q28.1 （P = 8 × 10−4）和2p21 (P = 0.02)）上观察到nsCL/P DNMs的显著富集，表明这些位点上的常见和罕见变异都趋同。我们还将dnm映射到指示转录因子（TF）结合的810个位置权重矩阵，并量化了等位基因变化对硅的影响。这表明，位于TF Musculin （MSC）核心结合区序列的dnm在名义上具有显著的过代表性（p = 0.037），对结合强度的影响更大。值得注意的是，MSC与一组位于GWAS位点的nsCL/P基因一起参与了面部肌肉的发育。单细胞转录组学数据和分子结合分析的其他结果支持了这一结论，表明MSC结合位点的变化有助于nsCL/P的病因学。我们的研究描述了一套可用于增加WGS数据附加值的方法。全基因组测序（WGS）数据的分析有很大的潜力来促进我们对共同性状遗传结构的理解。通过对伴有/不伴有腭裂的非综合征性唇裂的WGS数据应用一套系统的方法，我们在这里对其病因产生了新的见解。
Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a highly heritable facial disorder. To date, systematic investigations of the contribution of rare variants in non-coding regions to nsCL/P etiology are sparse. Here, we re-analyzed available whole-genome sequence (WGS) data from 211 European case-parent trios with nsCL/P and identified 13,522 de novo mutations (DNMs) in nsCL/P cases, 13,055 of which mapped to non-coding regions. We integrated these data with DNMs from a reference cohort, with results of previous genome-wide association studies (GWASs), and functional and epigenetic datasets of relevance to embryonic facial development. A significant enrichment of nsCL/P DNMs was observed at two GWAS risk loci (4q28.1 (p = 8 × 10−4) and 2p21 (p = 0.02)), suggesting a convergence of both common and rare variants at these loci. We also mapped the DNMs to 810 position weight matrices indicative of transcription factor (TF) binding, and quantified the effect of the allelic changes in silico. This revealed a nominally significant overrepresentation of DNMs (p = 0.037), and a stronger effect on binding strength, for DNMs located in the sequence of the core binding region of the TF Musculin (MSC). Notably, MSC is involved in facial muscle development, together with a set of nsCL/P genes located at GWAS loci. Supported by additional results from single-cell transcriptomic data and molecular binding assays, this suggests that variation in MSC binding sites contributes to nsCL/P etiology. Our study describes a set of approaches that can be applied to increase the added value of WGS data. The analysis of whole-genome sequencing (WGS) data has great potential to advance our understanding of the genetic architecture of common traits. By applying a set of systematic approaches to WGS data for non-syndromic cleft lip with/without cleft palate, we here generate novel insights into its etiology.
登录
查看更多内容
影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
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：
3.5
作者：
Ludwig KU;Böhmer AC;Bowes J;Nikolic M;Ishorst N;Wyatt N;Hammond NL;Gölz L;Thieme F;Barth S;Schuenke H;Klamt J;Spielmann M;Aldhorae K;Rojas-Martinez A;Nöthen MM;Rada-Iglesias A;Dixon MJ;Knapp M;Mangold E
通讯作者：
Mangold E
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
30.8
作者：
Birnbaum, Stefanie;Ludwig, Kerstin U.;Mangold, Elisabeth
通讯作者：
Mangold, Elisabeth