Beaty. Oral Clefts - Moving from Genome-Wide Studies Toward Functional Genomics

We will follow up on signals from a genome wide association study (GWAS) of oral clefts now being conducted with support from U01-DE-004425; "International Consortium to Identify Genes & Interactions Controlling Oral Clefts", 2007-2009; TH Beaty, PI). Oral clefts are among the most common human birth defects and have a complex and heterogeneous etiology. Genotyping for this project should be completed in early 2009, and our analysis will identify genes influencing risk directly, those acting only in the presence of an environmental risk factor, and/or genes showing measurable parent-of-origin effects which may represent imprinting. In this response to the FaceBase initiative (RFA-DE-09-003), we will build upon our GWAS results by using high throughput sequencing (HTS) techniques on genes/regions yielding statistical evidence of linkage and disequilibrium in the GWAS. We will first focus on genes identified through analysis of single nucleotide polymorphic (SNP) markers from our GWAS and will use HTS to identify all variants (rare mutations and novel markers) that may be causal, directly or indirectly. We will then undertake a systematic analysis of intensity data and the 60,000 markers in regions of known copy number variants (CNV) available on this platform to test genes that may influence risk through structural variation.

本研究将跟进一项由U01-DE-004425项目资助、目前正在开展的唇腭裂全基因组关联研究（Genome-Wide Association Study, GWAS）的关联信号；该研究为"识别控制唇腭裂的基因及相互作用国际联盟"（2007-2009年，TH Beaty为首席研究员）。唇腭裂是人类最常见的出生缺陷之一，其病因复杂且具有异质性。本项目的基因分型工作将于2009年初完成，我们的分析将直接识别影响发病风险的基因、仅在环境风险因素存在时才发挥作用的基因，以及表现出可检测的亲本起源效应（可能代表基因组印记）的基因。针对FaceBase倡议（RFA-DE-09-003）的本次响应研究，我们将基于前期GWAS结果，对该GWAS中呈现连锁不平衡统计证据的基因/区域采用高通量测序（High-Throughput Sequencing, HTS）技术进行后续分析。我们首先将聚焦于通过GWAS的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）标记分析所识别的基因，并利用HTS技术筛选所有可能直接或间接致病的变异（包括罕见突变与新型标记）。随后，我们将对该平台中已知拷贝数变异（Copy Number Variant, CNV）区域的强度数据与60,000个标记进行系统性分析，以验证可能通过结构变异影响发病风险的基因。