Genetics of Foot Disorders

描述（由申请人提供）：足部疾病影响了大约20-60%的美国人，并且越来越多地与慢性活动受限和残疾联系在一起。尽管遗传学的重要性被普遍怀疑，但尚未进行足部疾病的连锁、候选基因关联或全基因组关联研究（GWAS）。我们从弗雷明汉足部研究（弗雷明汉心脏研究[FHS]的辅助研究）中获得的初步数据显示，拇外翻具有很高的遗传性，尤其是在女性中。我们现在有独特的机会将特定足部疾病和足部生物力学数据与FHS和约翰斯顿县OA项目（JoCo OA）的大量遗传数据联系起来，这是两个基于社区的队列。通过确定可能导致晚年功能限制的足部疾病的遗传联系，可以应用有针对性的预防性干预措施，以防止或减缓功能丧失。本研究的主要目的是确定拇外翻、平足、空足、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：压力偏移中心指数（CPEI）和足底峰值负荷。具体而言，我们建议：1)扩大我们对FHS中这些特定足部性状遗传力的认识；2)进行GWAS荟萃分析以识别遗传变异；3)在独立样本中重复研究结果。足部生物力学测量的遗传力将在FHS中通过方差成分分析使用系谱结构来估计。一项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（白种人）的结果，然后（在计算机上）复制广泛性骨关节炎遗传学（GOGO）研究（白种人）中可用表型的单核苷酸多态性（snp），相关检验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非洲裔美国人中位于复制全基因组相关区域/位点的snp进行关联分析。建议的工作包括二次数据分析，使用我们目前nih资助的研究（RO1 AR047853）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。该建议利用现有独特的临床、流行病学、生物力学和遗传数据，这些数据来自两个大型、长期以社区为基础的队列。该提案利用了富有成效的流行病学、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、有效的足部数据和特征良好的遗传数据的唯一数据源。因此，这些研究人员独特地准备检查成人足部疾病的遗传学。

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.