Genetics of Foot Disorders

描述（由申请人提供）：足部疾病影响大约20-60%的美国人，并且越来越多地与慢性活动受限和残疾有关。虽然遗传学的重要性是普遍怀疑，没有连锁，候选基因关联，或全基因组关联研究（GWAS）足部疾病已进行。我们来自Frachial Foot研究（Frachial Heart研究[FHS]的辅助研究）的初步数据显示，拇外翻具有高遗传性，尤其是女性。我们现在有一个独特的机会，将特定足部疾病和足部生物力学的数据与FHS和约翰斯顿县OA项目（JoCo OA）中丰富的遗传数据联系起来，这两个项目是以社区为基础的队列。通过确定与足部疾病的遗传联系，可以在以后的生活中导致功能限制，有针对性的预防干预措施可以应用于预防或减缓功能丧失的目标。这项拟议研究的主要目的是确定拇外翻、扁平足、高弓足、小脚趾畸形（锤状趾、爪状趾或重叠趾）的遗传决定因素，以及足部生物力学指标：压力中心偏移指数（CPEI）和峰值足底负荷。具体来说，我们建议：1）扩大我们对FHS中这些特定足部特征的遗传性的了解; 2）进行GWAS荟萃分析以识别遗传变异; 3）在独立样本中复制研究结果。将在FHS中使用谱系结构通过方差分量分析估计足部生物力学测量值的遗传性。关于足部疾病和生物力学的GWAS荟萃分析将结合FHS和JoCo OA研究（高加索人）的联合收割机结果，然后复制（计算机模拟）单核苷酸多态性（SNP），其中泛发性骨关节炎遗传学（GOGO）研究（高加索人）中可用表型的关联检验p值小于10-5。为了评估我们研究结果的普遍性，我们将对JoCo OA中非洲裔美国人中位于复制的全基因组相关区域/位点的SNP进行关联分析。拟议的工作涉及二次数据分析，使用我们目前NIH资助的研究（RO 1 AR 047853）中的足部疾病和生物力学特征，在两个队列中使用相同的方案。该提案利用了来自两个大型、长期社区队列的现有独特临床、流行病学、生物力学和遗传数据。该提案利用了生产流行病学，生物力学和遗传学研究人员之间的良好合作，以及（据我们所知）特定，有效的足部数据和良好表征的遗传数据的唯一数据来源。因此，这些研究人员是唯一准备检查成人足部疾病的遗传学。 公共卫生相关性：足部疾病在人群中极为常见，并导致残疾和生活质量下降。其中许多在家庭中运行，表明遗传起源。重要的是要确定那些谁有这些条件，或在高风险发展，因为有效的干预措施存在，并可以针对适当的个人，以减少其影响或潜在地防止其发展。

DESCRIPTION (provided by applicant): Foot disorders affect approximately 20-60% of Americans and are increasingly linked to chronic mobility limitations and disability. Although the importance of genetics is commonly suspected, no linkage, candidate gene association, or genome-wide association studies (GWAS) on foot disorders have been performed. Our preliminary data from the Framingham Foot Study (an ancillary of the Framingham Heart Study [FHS]) show high heritability of hallux valgus, especially in women. We now have the unique opportunity to link data on specific foot disorders and foot biomechanics to a wealth of genetic data in the FHS and the Johnston County OA Project (JoCo OA), two community-based cohorts. By identifying genetic links to foot disorders which can cause functional limitations in later life, targeted preventive interventions can be applied with the goal of preventing or slowing functional loss. The primary objective of this proposed study is to identify genetic determinants of hallux valgus, pes planus, pes cavus, lesser toe deformities (hammer toes, claw toes, or overlapping toes), and foot biomechanics measures: the Center of Pressure Excursion Index (CPEI), and peak plantar load. Specifically, we propose to 1) expand our knowledge of the heritability of these specific foot traits in the FHS; 2) perform a GWAS meta-analysis to identify genetic variants; and 3) replicate the findings in independent samples. Heritability of foot biomechanics measurements will be estimated in the FHS using pedigree structure by a variance component analysis. A GWAS meta-analysis on foot disorders and biomechanics will combine results from FHS and JoCo OA studies (Caucasians) and then replicate (in-silico) the Single Nucleotide Polymorphisms (SNPs) with association test p-values less than 10-5 for available phenotypes in the Genetics of Generalized Osteoarthritis (GOGO) Study (Caucasians). To assess the generalizability of our findings, we will perform association analysis for those SNPs located in the replicated genome-wide associated regions/loci, in African Americans in JoCo OA. The proposed work involves secondary data analysis, using foot disorders and biomechanical traits from our current NIH-funded Study (RO1 AR047853) using identical protocols in both cohorts. This proposal leverages existing unique clinical, epidemiological, biomechanical and genetic data from two large, long-standing community-based cohorts. The proposal capitalizes upon well-established collaborations between productive epidemiologic, biomechanics, and genetics investigators and (to our knowledge) the only data sources of both specific, valid foot data and well-characterized genetic data. These investigators are thus uniquely poised to examine the genetics of foot disorders in adults. PUBLIC HEALTH RELEVANCE: Foot disorders are extremely common in the population and contribute to disability and diminished quality of life. Many of these run in families, suggesting a genetic origin. It is important to identify those who have these conditions, or are at high risk to develop them, because effective interventions exist and can be targeted to appropriate individuals to lessen their impact or potentially prevent their development.