Study designs to enhance identification of genetic factors in healthy aging

The sequencing of the human genome and the growing understanding of its function are providing powerful new research tools for identifying genetic variants that are associated with complex diseases and traits. Somewhat less emphasis has been given to genes related to healthy aging, although the approaches for studying health-related traits are analogous to those used for disease-related studies. A critical step prior to the design of such studies is to define a healthy aging phenotype, which should be standardized to permit comparisons across studies and should involve more than simple longevity. Phenotypes of particular value for genetic research are those with high heritability and close relationships to gene products or pathways, preferably with minimal or at least measurable environmental influences. Appropriate study designs to identify genotype-phenotype associations include family-based linkage studies, candidate gene association analyses, and genome-wide association studies. Advances in genotyping and sequencing technologies, and the generation of the human haplotype map database, now permit the cost-effective investigation of the very large sample sizes needed for genome-wide association studies in unrelated individuals. Challenges in interpretation and translation of such studies include assessing the potential for bias and confounding, as well as determining the clinical validity and utility of findings proposed for wider application. Many such studies are currently supported or being planned across the National Institutes of Health (NIH), and lend themselves to the kind of coordinated clinical research envisioned in programs such as the NIH Roadmap.