High Throughput Genotyping and DNA Sequencing for Studying the Genetic Contributions to Human Disease: Genetic Analysis of Metopic Nonsyndromic Craniosynostosis (Boyadjiev Boyd)

用于研究人类疾病遗传贡献的高通量基因分型和 DNA 测序：异位非综合征性颅缝早闭的遗传分析 (Boyadjiev Boyd)

• 批准号: 10023797
• 负责人: KIM DOHENY
• 金额: $ 12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-03 至 2021-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023797
• 关键词: Affect; BMP2 gene; Biological; Biological Assay; Candidate Disease Gene; Caucasians; Collaborations; Congenital Abnormality; Craniosynostosis; DNA sequencing; Defect; Developmental Delay Disorders; Disease; Dizygotic Twins; Etiology; Family; Family Study; Female; Fibroblast Growth Factor Receptors; Frequencies; Funding; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genome; Genotype; Individual; Infant; International; Joint structure of suture of skull; Live Birth; Minor; Molecular; Mutation; Not Hispanic or Latino; Parents; Phenotype; Positioning Attribute; Prevention; Prevention strategy; Primary Prevention; Privatization; Recurrence; Research; Resources; Risk; Role; Sampling; Skeletal Development; Specimen; Surgical sutures; Variant; Work; base; case control; causal variant; cost; cranium; design; exome; experience; experimental study; genetic analysis; genetic variant; genome wide association study; human disease; insight; interest; male; next generation sequencing; population based; premature; targeted sequencing; trait; whole genome

Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a common defect occurring in 1 in 2,500 live births. About 85% of infants with CS present as nonsyndromic (i.e., without unrelated, major birth defects or developmental delay). Nonsyndromic CS (NCS) is a heterogeneous condition with presumed multifactorial etiology; however, its causes remain largely unknown. As such, primary prevention strategies for this defect are limited. Through our International Craniosynostosis Consortium (ICC), we have advanced the understanding of the genetic etiology for the most common NCS subtype, sagittal NCS (sNCS). As a result of our previous funding (R01 DE016866), we successfully conducted the first genome-wide association study (GWAS) for sNCS and identified robust associations to loci near BMP2 (rs1884302; P=1.1x10-39; OR=4.38) and intronic to BBS9 (rs10262453; P=5.6x10-20; OR=0.24), both biologically plausible genes with a role in skeletal development. Building on our work, we hypothesize that the identified variants contribute to the risk of NCS by altering gene expression. In this application we propose to investigate 400 case-parent trios with metopic NCS (mNCS) by GWAS. Both sNCS and mNCS affect the midline sutures of the skull, are more likely to occur among non-Hispanic whites, and show a male excess. Given these similarities, we hypothesize that sNCS and mNCS may share common causative variants and propose an array-based family study of mNCS case-parent trios and replication with independent case-control samples. Next generation sequencing and functional assays of candidate genes and loci identified in GWAS of mNCS will be conducted together with those for sNCS. In summary, the current proposal represents an extension of our current study aimed to perform a comprehensive molecular characterization of sNCS and mNCS. Given our accomplishments and substantial resources of the ICC and the previous collaboration with the Center for Disease Research (CIDR), we are well-positioned to successfully complete the proposed research and contribute critical insights into the multifactorial etiology of sNCS and mNCS.

颅缝早闭（CS），一个或多个颅缝的过早融合，是一种常见的缺陷，发生在1/2500活产。大约85%的CS婴儿表现为非综合征（即，没有不相关的重大出生缺陷或发育迟缓）。非综合征性CS（NCS）是一种异质性疾病，推测病因是多因素的，然而，其原因仍在很大程度上未知。因此，这种缺陷的一级预防策略是有限的。通过我们的国际颅缝早闭联合会（ICC），我们对最常见的NCS亚型矢状面NCS（sNCS）的遗传病因学有了进一步的了解。由于我们之前的资助（R 01 DE 016866），我们成功地进行了sNCS的第一个全基因组关联研究（GWAS），并鉴定了与BMP 2附近基因座的强关联性。（rs 1884302; P=1.1x10-39; OR=4.38）和BBS 9的内含子（rs 10262453; P=5.6x10-20; OR=0.24），这两个基因在生物学上都是合理的，在骨骼发育中发挥作用。基于我们的工作，我们假设所鉴定的变异通过改变基因表达而导致NCS的风险。在本申请中，我们提出了调查400例父母三胞胎与异位NCS（mNCS）的GWAS。sNCS和mNCS都影响颅骨的中线缝，更有可能发生在非西班牙裔白人中，并显示男性过剩。鉴于这些相似之处，我们假设sNCS和mNCS可能有共同的致病变异，并提出了一个基于阵列的mNCS病例-父母三人组和独立病例对照样本复制的家庭研究。mNCS的GWAS中鉴定的候选基因和位点的下一代测序和功能测定将与sNCS的测序和功能测定一起进行。总之，目前的建议代表了我们目前研究的扩展，旨在对sNCS和mNCS进行全面的分子表征。鉴于我们在ICC取得的成就和大量资源以及之前与疾病研究中心（CIDR）的合作，我们完全有能力成功完成拟议的研究，并为sNCS和mNCS的多因素病因提供重要见解。