Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.
Imputation of orofacial clefting data identifies novel risk loci and sheds light on the genetic background of cleft lip ± cleft palate and cleft palate only.
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DOI：
10.1093/hmg/ddx012
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发表时间：
2017-02-15
影响因子：
3.5
通讯作者：
Mangold E
中科院分区：
文献类型：
--
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
非综合征性唇腭裂（nsCL/P）是人类最常见的出生缺陷之一，具有多因素病因。在这里，我们提出了来自nsCL/P的全基因组插补研究的结果，其中，在添加复制队列数据后，确定了nsCL/P的四个新的风险位点（在染色体区域2 p21，14 q22，15 q24和19 p13）。在一个系统的水平上，我们表明，在这个高密度数据集内的关联信号是丰富的功能相关的基因组区域，活跃在人类神经嵴细胞（hNCC）和小鼠胚胎颅面组织。这种富集在为以后的活性准备的hNCC区域中也是可检测的。使用GCTA分析，我们认为欧洲人群中nsCL/P风险的估计方差的30%可归因于常见变异，其中25.5%由迄今已知的24个风险位点贡献。对于每一个这些，我们确定可信的单核苷酸多态性使用贝叶斯细化的方法，两个位点窝藏只有一个可能的因果变异。最后，我们证明，有没有多基因组件nsCL/P检测，是共享非综合征腭裂（nsCPO）。我们的数据表明，虽然常见变异对nsCL/P的风险有很大贡献，但它们似乎不参与nsCPO，而nsCPO可能更常见于罕见的有害变异。我们的研究产生了新的见解nsCL/P和nsCPO病因，并提供了一个系统的框架，研究颅面发育和畸形。
Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.