Corrigendum: Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.

[This corrects the article on p. 179 in vol. 7, PMID: 27790247.].

Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.

This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.

How Genes Modulate Patterns of Aging-Related Changes on the Way to 100: Biodemographic Models and Methods in Genetic Analyses of Longitudinal Data.

BACKGROUND AND OBJECTIVE: To clarify mechanisms of genetic regulation of human aging and longevity traits, a number of genome-wide association studies (GWAS) of these traits have been performed. However, the results of these analyses did not meet expectations of the researchers. Most detected genetic associations have not reached a genome-wide level of statistical significance, and suffered from the lack of replication in the studies of independent populations. The reasons for slow progress in this research area include low efficiency of statistical methods used in data analyses, genetic heterogeneity of aging and longevity related traits, possibility of pleiotropic (e.g., age dependent) effects of genetic variants on such traits, underestimation of the effects of (i) mortality selection in genetically heterogeneous cohorts, (ii) external factors and differences in genetic backgrounds of individuals in the populations under study, the weakness of conceptual biological framework that does not fully account for above mentioned factors. One more limitation of conducted studies is that they did not fully realize the potential of longitudinal data that allow for evaluating how genetic influences on life span are mediated by physiological variables and other biomarkers during the life course. The objective of this paper is to address these issues. DATA AND METHODS: We performed GWAS of human life span using different subsets of data from the original Framingham Heart Study cohort corresponding to different quality control (QC) procedures and used one subset of selected genetic variants for further analyses. We used simulation study to show that approach to combining data improves the quality of GWAS. We used FHS longitudinal data to compare average age trajectories of physiological variables in carriers and non-carriers of selected genetic variants. We used stochastic process model of human mortality and aging to investigate genetic influence on hidden biomarkers of aging and on dynamic interaction between aging and longevity. We investigated properties of genes related to selected variants and their roles in signaling and metabolic pathways. RESULTS: We showed that the use of different QC procedures results in different sets of genetic variants associated with life span. We selected 24 genetic variants negatively associated with life span. We showed that the joint analyses of genetic data at the time of bio-specimen collection and follow up data substantially improved significance of associations of selected 24 SNPs with life span. We also showed that aging related changes in physiological variables and in hidden biomarkers of aging differ for the groups of carriers and non-carriers of selected variants. CONCLUSIONS: . The results of these analyses demonstrated benefits of using biodemographic models and methods in genetic association studies of these traits. Our findings showed that the absence of a large number of genetic variants with deleterious effects may make substantial contribution to exceptional longevity. These effects are dynamically mediated by a number of physiological variables and hidden biomarkers of aging. The results of these research demonstrated benefits of using integrative statistical models of mortality risks in genetic studies of human aging and longevity.

Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (< 5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases.

Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study.

OBJECTIVES: To compare how well frailty measures based on a phenotypic frailty approach proposed in the Cardiovascular Health Study (CHS) and a cumulative deficits approach predict mortality. DESIGN: Cohort study. SETTING: The main cohort of the CHS. PARTICIPANTS: Four thousand seven hundred twenty-one individuals. MEASUREMENTS: A phenotypic frailty index (PFI) was defined in the same way as proposed in the CHS: assessing weight loss, exhaustion, low physical activity, slowness, and poor grip strength. A cumulative deficit index (DI) was defined based on 48 elderly deficits (signs, symptoms, impairments, diseases) included in the index, with equal weights. RESULTS: Of the 1,073 frailest individuals with the lowest survival, the PFI, categorized as proposed in the CHS into robust, prefrail, and frail categories, underestimated the risk of death for 720 persons, whereas the DI categorized into the same three frailty categories underestimated the mortality risk for 134 persons. The higher power of the DI for discriminating frail individuals in their susceptibility to death also followed from comparison of quasi-instantaneous values of both indices. The three-level DI identified 219 individuals as frail of 361 individuals identified as frail according to the three-level PFI. CONCLUSION: The DI can more precisely evaluate chances of death because it assesses a broader spectrum of disorders than the PFI. Both indices appear to be frailty related. Integration of both approaches is highly promising for increasing the precision of discrimination of the risk of death and especially for identification of the most vulnerable elderly people.

An inverse association between self-reported arthritis and mortality in the elderly: findings from the national long-term care survey.

Major musculoskeletal conditions including arthritis represent an increasing burden on individuals and societies. We analyzed the association between self-reported arthritis and mortality in the U.S. elderly disabled and non-disabled individuals using unique disability-focused data from the large-scale population-based National Long Term Care Survey. It was found that males and females who reported arthritis/rheumatism have, generally, smaller risks of death than those who did not report those conditions. This inverse relationship is more pronounced in disabled individuals. This finding holds for both short-term (relative risk [RR] = 0.81; 95% confidence interval [CI] = 0.75-0.88 for males and RR = 0.76; CI = 0.71-0.82 for females) and long-term follow-ups (RR = 0.82; CI = 0.78-0.87 for males and RR = 0.83; CI = 0.79-0.87 for females). For females, this effect is age insensitive, while for males it is limited to ages below 85. Demographic and 19 major self-reported geriatric conditions have trivial effect on these risks, supporting the view that a better survival of diseased individuals can be attributed to the effects of medical treatment. Given the widespread prevalence of arthritis/rheumatism and disability in elderly populations and the increasing population of the elderly, these findings call for comprehensive analyses of factors driving better survival and medical costs associated with extended lives.

Body mass index and nine-year mortality in disabled and nondisabled older U.S. individuals.

OBJECTIVES: To investigate the relationship between body mass index (BMI) and 9-year mortality in older (> or = 65) Americans with and without disability. DESIGN: Cohort study. SETTING: The unique disability-focused National Long Term Care Survey (NLTCS) data that assessed the health and well-being of older individuals in 1994 were analyzed. PARTICIPANTS: Four thousand seven hundred ninety-one individuals in the 1994 survey. MEASUREMENTS: BMI (kg/m2) was calculated from self- or proxy reports of height and weight. The analysis was adjusted for 1-year change in BMI and demographic and health-related factors, as well as reports by proxies, and death occurring during the first 2 years after the interview. RESULTS: The relative risk of death as a function of BMI formed a nonsymmetric U-shaped pattern, with larger risks associated with lower BMI (< 22.0) and minimal risks for BMI of 25.0 to 34.9. (BMI 22.0-24.9 was the reference.) Adjustments for demographic and health-related factors had little effect on this pattern. Nondisabled individuals exhibited a similar U-shaped pattern but with lower risks associated with lower BMI. For disabled individuals, the mortality-risk pattern was higher for lower BMI (< 22.0) and flat for higher BMI, thus exhibiting an inverse J shape. BMI patterns were age sensitive, with disability status affecting sensitivity. CONCLUSION: Overweight or mild (grade 1) obesity was not a risk factor for 9-year mortality in older Americans participating in the 1994 NLTCS. A flatter BMI pattern of the relative risk of death for disabled than for nondisabled individuals suggests that optimal body weight can be sensitive to age and health and well-being.