Functional Validation of Noncoding Variants Associated With Nonsyndromic Orofacial Cleft

IF 3.7 2区 医学 Q2 GENETICS & HEREDITY
Siying Zhu, Hongxu Tao, Robert A. Cornell, Huan Liu
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Abstract

Over the past decade, genome-wide association studies (GWASs) have found genetic variants associated with elevated risk for nonsyndromic orofacial cleft (NSOFC). In the post-GWAS era of NSOFC genetic research, an important aim is to identify the pathogenic variants that influence craniofacial development processes, towards understanding how they lead to disease manifestation. However, two major challenges hinder the translation of GWAS results into a mechanistic understanding. Firstly, it is uncertain whether the variants pinpointed by GWAS represent the underlying pathogenic variants; secondly, the bulk of genetic variants identified through GWAS are situated in noncoding regions of the genome, complicating their biological interpretation. Presently, research on noncoding genetic variants associated with NSOFC predominantly centers on variants located in transcriptional regulatory elements. These variants modulate transcription, subsequently altering the expression of downstream target genes and disrupting gene regulatory networks. We provide a systematic summary of the recent NSOFC-associated GWAS findings for the first time. With a particular focus on variants located in noncoding regions, we delve into current statistical methods and functional approaches for identifying and validating causal variants, aiming to bridge the gap between genetic variants identified by GWAS and their underlying pathogenic mechanism responsible for NSOFC. Deciphering causal variants underlying NSOFC offers valuable clinical insights that may advance early diagnosis, enhance risk stratification, and facilitate the discovery of novel therapeutic targets.

Abstract Image

与非综合征性口面裂相关的非编码变异的功能验证
在过去的十年中,全基因组关联研究(GWASs)已经发现了与非综合征性口面部唇裂(NSOFC)风险升高相关的遗传变异。在后gwas时代,NSOFC基因研究的一个重要目标是确定影响颅面发育过程的致病变异,以了解它们如何导致疾病表现。然而,两个主要的挑战阻碍了将GWAS结果转化为机制理解。首先,不确定GWAS确定的变异是否代表潜在的致病变异;其次,通过GWAS鉴定的大部分遗传变异位于基因组的非编码区域,使其生物学解释复杂化。目前,对与NSOFC相关的非编码遗传变异的研究主要集中在转录调控元件上。这些变异调节转录,随后改变下游靶基因的表达并破坏基因调控网络。我们首次系统总结了最近与nsofc相关的GWAS发现。我们特别关注位于非编码区域的变异,深入研究了目前用于识别和验证因果变异的统计方法和功能方法,旨在弥合GWAS识别的遗传变异与其导致NSOFC的潜在致病机制之间的差距。破译NSOFC的因果变异提供了有价值的临床见解,可以促进早期诊断,加强风险分层,并促进发现新的治疗靶点。
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来源期刊
Human Mutation
Human Mutation 医学-遗传学
CiteScore
8.40
自引率
5.10%
发文量
190
审稿时长
2 months
期刊介绍: Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.
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