We will exploit the multicenter Long Life Family Study (LLFS), a unique resource for research on human longevity and healthy aging, to find genetic variants associated with these traits. In the current period, we successfully enrolled and extensively phenotyped 4,953 individuals in 539 two-generational families that demonstrate clustering for exceptional survival in the upper generation. Fewer than 1% of the Framingham Heart Study (FHS) families (a roughly random sample of families) would meet the minimal entrance criteria for exceptional survival required in the LLFS. Thus our least exceptional families show more clustering for exceptional longevity than 99% of the Framingham families. Further, the children's generation have significantly lower rates of major diseases of aging including diabetes, chronic pulmonary disease, peripheral artery disease and show significantly more favorable profiles of quantitative mariners of healthy aging such as blood pressure, lipids, functional performance, and cognitive indices compared to FHS. These endophenotypes show greater clustering (with high heritability) in the LLFS familiesthan in FHS. Thus, LLFS has likely greatly enriched the prevalence of any gene variants for longevity and healthy aging endophenotypes, thereby increasing detection power. Most importantly, the family design of LLFS provides additional power and analytic opportunities to discover genetic influences than would be possible in a study of unrelated individuals, especially with regard to rare alleles.
Our specific aims are to: 1) continue phenotyping by assaying biomarkers of healthy aging on stored samples, annually tracking subjects for new significant medical and health events, and comparing Medicare (and Danish equivalent) disease and utilization data with reference samples;2) identiy common genetic variants for healthy aging and excepional survival using GWAS;3) identify rare variants for exceptional survival and healthy aging by targeted sequencing;and 4) more clearly dissect the genetic architecture of exceptional survival an healthy aging through a systems approach involving genet networks and pathways, to better understand the complex interplay between genetic variants, exposures, and covariates in the development of endophenotypes. Taking a multidisciplinary approach involving clinicians, demographers, geneticists, epidemiologists, and computational scientists, we propose to capitalize on the investments already made in creating this unique cohort to further our understanding of the nature of exceptional survival and healthy aging.
Exceptional longevity and healthy aging are highly enriched in the families enrolled in the LLFS thus allowing us a unique opportunity to discover both common and rare genetic associations with these traits. Such associations will not only markedly enhance our understanding of why some people age so much better than others, but will also lead to enhanced prognostication for healthy and unhealthy aging and potentially disease prevention strategies.
|Daw, E Warwick; Hicks, James; Lenzini, Petra et al. (2018) Methods for detecting methylation by SNP interaction in GAW20 simulation. BMC Proc 12:37|
|Sung, Yun J (see original citation for additional authors) (2018) A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. Am J Hum Genet 102:375-400|
|Marron, Megan M; Singh, Jatinder; Boudreau, Robert M et al. (2018) A novel healthy blood pressure phenotype in the Long Life Family Study. J Hypertens 36:43-53|
|Sebastiani, Paola; Thyagarajan, Bharat; Sun, Fangui et al. (2017) Biomarker signatures of aging. Aging Cell 16:329-338|
|Polimanti, Renato; Jensen, Kevin P; Gelernter, Joel (2017) Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers. Sci Rep 7:1034|
|Lam, Max; Trampush, Joey W; Yu, Jin et al. (2017) Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets. Cell Rep 21:2597-2613|
|Macé, Aurélien; Tuke, Marcus A; Deelen, Patrick et al. (2017) CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nat Commun 8:744|
|Fagan, Erin; Sun, Fangui; Bae, Harold et al. (2017) Telomere length is longer in women with late maternal age. Menopause 24:497-501|
|Barral, Sandra; Singh, Jatinder; Fagan, Erin et al. (2017) Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities. J Gerontol A Biol Sci Med Sci 72:1683-1688|
|Sebastiani, Paola; Thyagarajan, Bharat; Sun, Fangui et al. (2016) Age and Sex Distributions of Age-Related Biomarker Values in Healthy Older Adults from the Long Life Family Study. J Am Geriatr Soc 64:e189-e194|
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