Genomic and Metabolomic Profiling of Finnish Familial Dyslipidemia Families

芬兰家族性血脂异常家族的基因组和代谢组学分析

• 批准号: 8644877
• 负责人: NELSON B. FREIMER
• 金额: $ 69.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644877
• 关键词: Atherosclerosis; Bioinformatics; Biological; Biological Assay; Biological Process; Biology; Blood; Blood specimen; Cataloging; Catalogs; Chromosome Mapping; Collection; Complex; Data; Disease; Dyslipidemias; Enrollment; Familial Combined Hyperlipidemia; Family; Family Study; Family member; Finland; Founder Generation; Frequencies; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genetic Variation; Genome Scan; Genomics; Genotype; Grant; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Individual; Investigation; Knowledge; Light; Lipids; Lipoproteins; Literature; Location; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Diseases; Metabolism; Methods; Mutation; National Heart, Lung, and Blood Institute; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Pathologic; Pattern; Phenotype; Population; RNA Sequences; Rare Diseases; Resolution; Resources; Rest; Risk; SNP genotyping; Sampling; Serum; Staging; Structure; Study Subject; Susceptibility Gene; Technology; Validation; Variant; base; cardiovascular disorder risk; cohort; gene function; genetic linkage analysis; genetic pedigree; genetic variant; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; lipid metabolism; member; metabolomics; novel; peripheral blood; professor; rare variant; risk variant; segregation; standard measure; success; trait

DESCRIPTION (provided by applicant): This proposal is to re-investigate, using metabolomic profiling and advanced genomics technologies, 92 Finnish pedigrees that were ascertained for two forms of complex heritable dyslipidemia: familial combined hyperlipidemia (FCHL) and low serum levels of high density lipoprotein cholesterol (HDL-C). These families were extensively phenotyped for metabolic measures and while linkage analyses yielded strong findings for FCHL and HDL-C in several chromosomal locations, identification of causal variants had been limited by the lack of sufficiently powerful technologies for both phenotypic and genotypic characterization. We now propose to re-analyze these families by obtaining new phenotypes hypothesized to more accurately reflect the biological underpinnings of dyslipidemias than the previously used composite lipid measures. The unique population structure of Finland provides special advantages for discovery of low frequency and rare disease- related variants in these families and opportunities for further validation of findings in several Finnish population cohorts In this project we will obtain metabolomic profiles on about 1400 members of these pedigrees. By combining whole genome sequencing (WGS) of the most genetically informative family members (about 300 individuals) with genome wide SNP genotyping of the entire pedigrees, we will establish a comprehensive catalog of variants segregating in these pedigrees. Phenotype-genotype correlations established by linkage and association analyses, along with bioinformatic analyses that detect likely deleterious variants, will enable us to identify the specific variants hat are candidates for contributing to the original and expanded set of metabolic phenotypes that we will obtain. Gene expression data to be obtained by RNA sequencing of blood samples from all available pedigree members (estimated to be about 900 individuals) will provide an additional form of evidence to prioritize candidate variants for metabolic phenotypes and may suggest relationships between genetic variation and gene function.

描述（由申请人提供）：本提案旨在利用代谢组学分析和先进的基因组学技术，重新研究 92 个芬兰家系，这些家系被确定为两种形式的复杂遗传性血脂异常：家族性联合高脂血症 (FCHL) 和低血清水平的高密度脂蛋白胆固醇 (HDL-C)。对这些家族进行了广泛的代谢测量表型分析，虽然连锁分​​析在几个染色体位置的 FCHL 和 HDL-C 方面取得了强有力的发现，但由于缺乏足够强大的表型和基因型表征技术，导致因果变异的鉴定受到限制。我们现在建议通过获得新的表型来重新分析这些家族，这些新表型假设比以前使用的复合脂质测量更准确地反映血脂异常的生物学基础。芬兰独特的人口结构为发现这些家族中的低频和罕见疾病相关变异提供了特殊的优势，并为进一步验证几个芬兰人口队列的发现提供了机会。在这个项目中，我们将获得这些谱系中约 1400 名成员的代谢组学概况。通过将遗传信息最丰富的家庭成员（约 300 名个体）的全基因组测序 (WGS) 与整个谱系的全基因组 SNP 基因分型相结合，我们将建立这些谱系中分离的变异的综合目录。通过连锁和关联分析建立的表型-基因型相关性，以及检测可能有害变异的生物信息学分析，将使我们能够识别特定变异，这些变异是对我们将获得的原始和扩展的代谢表型集做出贡献的候选者。通过对所有可用谱系成员（估计约 900 人）的血液样本进行 RNA 测序获得的基因表达数据将提供另一种形式的证据，以优先考虑代谢表型的候选变异，并可能表明遗传变异和基因功能之间的关系。