Gene-SNP haplotype analysis of an aging population

随着整个人类基因组现在几乎完全解码，注意力正在转向个体遗传变异。这种变异大部分由单核苷酸多态性（SNP）组成，其可以解释例如疾病易感性和对药物的反应中的可遗传个体间差异。衰老是大多数常见人类疾病的主要风险因素。识别候选基因中的SNPs并评估其对衰老相关表型的潜在功能影响，对于评估衰老的遗传成分（包括异常健康的衰老）将非常重要。在这方面，最佳的研究人群是那些与衰老相关的表型可以根据从中年开始的进展来定义的人群，而不是作为时间的快照。这项建议的目的是 进一步优化先前开发的SNP发现方法，二维基因扫描（TDGS），以全面分析大型老龄化人群中多个候选基因的SNP。该方法的有效性将通过以病例对照方式对226名正在进行的老龄化纵向研究（圣安东尼奥老龄化纵向研究; SALSA）的墨西哥裔美国人个体中参与肌肉骨骼功能的核和线粒体基因的所有可能的SNP单倍型进行关联分析来评估。预计这些结果将丰富正在进行的研究，为这种特定的表型提供遗传成分，并证明TDGS作为高通量平台的有效性，以筛选数百甚至数千个候选基因中所有可能的SNP（综合候选方法）。

With the entire human genome now almost completely decoded, attention is shifting towards individual genetic variation. Most of this variation consists of single nucleotide polymorphisms (SNPs), which can account for heritable inter-individual differences in, for example, disease susceptibility and response to medication. Aging is a major risk factor for most common human diseases. The identification of SNPs in candidate genes and the assessment of their potential functional impact on aging-related phenotypes will be important in assessing genetic components of aging, including exceptionally healthy aging. Optimal study populations in this respect are those in which aging-related phenotypes can be defined in terms of their progression from middle age onwards, rather than as snapshots in time. The objective of this proposal is to further optimize a previously developed SNP discovery method, Two-Dimensional Gene Scanning (TDGS), to comprehensively analyze SNPs in multiple candidate genes in large, aging populations. The validity of this approach will be assessed through association analysis, in a case control manner, of all possible SNPhaplotypes of a selection of nuclear and mitochondrial genes involved in musculoskeletal function in a population of 226 Mexican American individuals of an ongoing longitudinal study of aging (San Antonio Longitudinal Study of Aging; SALSA). The results are expected to enrich the ongoing study with a genetic component for this particular phenotype and to demonstrate the validity of TDGS as a high-throughput platform to screen aging populations for all possible SNPs in hundreds and ultimately thousands of candidate genes (comprehensive candidate approach).