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Bone Microarchitecture: The Framingham Osteoporosis Study

骨微结构：弗雷明汉骨质疏松症研究

基本信息

批准号：
8631420
负责人：
DOUGLAS P. KIEL
金额：
$ 85.82万
依托单位：
HEBREW REHABILITATION CENTER FOR AGED
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631420
关键词：
Aging Alleles Bioinformatics Bone Density Candidate Disease Gene Chromatin Structure Clinic Code Complement Cost of Illness DNA Data Deterioration Disease Elements Encyclopedia of DNA Elements Epidemiology Exons Family Fracture Functional RNA Funding Gene Expression Profile Gene Frequency Genes Genetic Genetic Transcription Genome Genomics Genotype Gold Grant Heart Human Human Genetics Individual International Lead Maps Measures Meta-Analysis Minor Mutation Nucleic Acid Regulatory Sequences Open Reading Frames Osteoporosis Pathway interactions Peripheral Phenotype Proteins Public Health Quantitative Trait Loci Radial Reporting Research Resolution Risk Sampling Source Testing Tissue Sample Variant Work X-Ray Computed Tomography base bone bone cell bone health bone strength clinical practice cohort deep sequencing exome exome sequencing genetic variant genome sequencing genome wide association study genome-wide histone modification interest lifestyle factors male novel offspring parent grant population based public health relevance retiree tibia tool transcription factor

项目摘要

This supplement ("Revision") to our currently funded grant entitled, "Bone Microarchitecture: The Framingham Osteoporosis Study," expands the scope of the genetics work of the parent grant. It will extend the genome- wide association study (GWAS) of the parent grant to the realm of potentially more functional, less common variants that will provide important data on the contribution of these variants to bone microarchitecture measured by high resolution peripheral quantitative computed tomography (HR-pQCT). Ideally, the best way to identify potentially functional genetic variants associated with bone microarchitecture is to have sequencing data from as much of the genome as possible. Although deep sequencing represents a powerful approach for the discovery of the complete spectrum of variants that cause diseases, the cost of obtaining and analyzing whole genome or even exome-sequences on a large human sample remains prohibitive. Therefore, this study will make use of exome chip data along with dense genome wide genotyping data in several cohorts with HR- pQCT phenotypes to impute less common and potentially functional variants across the whole genome. The imputation will make use of a growing reference panel of whole genome sequencing that has emerged from several international efforts. To accomplish our aim, we have assembled all the cohorts from around the world who currently have HR-pQCT phenotypes and DNA available. The approach to be taken in this project will involve the following steps: 1) Use existing GWAS genotyping and exome chip genotyping from the family- based Framingham Study to impute variants with minor allele frequency as low as 0.5%; 2) Obtain the same GWAS and exome chip genotyping in three other cohorts with the identical HR-pQCT-derived bone microarchitecture phenotypes; 3) Perform the whole genome imputation in those population-based cohorts using an integrated reference panel consisting of 10,000 publicly available whole genome sequences; 4) Meta-analyze results from cohort specific association analyses using the imputed genotypes; 5) Prioritize the most significant findings in the meta-analyses, using statistical significance levels as well as bioinformatic tools to predict functional potential (e.g. ENCODE, eQTL analysis); 6) Validate the accuracy of the imputed variants having the most significant association with bone microarchitecture by performing de-novo genotyping in the Framingham Study; 7) Replicate the most significant associations for variants with confirmed accurate genotype in five other HR-pQCT cohorts using de-novo genotyping. Our strategy of identifying both common and less common, potentially causal variants in protein-coding regions and non-coding regulatory regions represents a robust conceptual paradigm for the study of bone microarchitectural deterioration that characterizes the disease, osteoporosis.

本补充（“修订”）是对我们目前资助的题为“骨微结构：Framingham”的资助