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Age-related diseases characteristic of post-reproductive life, aging, and life span are the examples of polygenic non-Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non-carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non-carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid- and immunity-related mechanisms, whereas the AD risk, can be driven by the AD-biomarker-related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

There is evidence on high prevalence of comorbidity in people with dementia and on associations between comorbidities and progression of Alzheimer’s disease (AD). Comorbidities accumulate with age and age is also a major risk factor for AD. Repeated measurements of comorbidity provide possibilities for gaining more knowledge about dynamic interconnection between comorbidities and AD development in the context of aging. We constructed the comorbidity index (CMI) for participants of the Health and Retirement Study aged 66+ years using data on onset of diseases from linked Medicare service use files (6,830 participants, 3,829 females, 3,001 males). We performed the joint analysis of longitudinal measurements of CMI and data on onset of AD and survival since onset of AD using the approach (the stochastic process model) that allows decomposing the overall association of trajectories of CMI with respective time-to-event outcomes into several aging-related characteristics represented by the model’s components and evaluated indirectly from the data. We found that, overall, CMI is significantly (p< 0.0001) associated with increased risk of onset of AD and decreased survival chances for persons with AD and that this association can be decomposed into associations of AD outcomes with different aging-related components with differentiated impact of genetic and non-genetic factors (such as APOE, polygenic scores, sex, birth cohort). In particular, age patterns and time trends in such components contribute to trends in AD prevalence so that taking into account the age dynamics and time trends in comorbidities (represented by CMI) is essential for forecasting future trends in AD prevalence.

Recently, Mahalanobis distance (DM) was suggested as a statistical measure of physiological dysregulation in aging individuals. We constructed DM variants using sets of biomarkers collected at the two visits of the Long Life Family Study (LLFS) and performed joint analyses of longitudinal observations of DM and follow-up mortality in LLFS using joint models. We found that DM is significantly associated with mortality (hazard ratio per standard deviation: 1.31 [1.16, 1.48] to 2.22 [1.84, 2.67]) after controlling for age and other covariates. GWAS of random intercepts and slopes of DM estimated from joint models found a genome-wide significant SNP (rs12652543, p=7.2 × 10-9) in the TRIO gene associated with the slope of DM constructed from biomarkers declining in late life. Review of biological effects of genes corresponding to top SNPs from GWAS of DM slopes revealed that these genes are broadly involved in cancer prognosis and axon guidance/synapse function. Although axon growth is mainly observed during early development, the axon guidance genes can function in adults and contribute to maintenance of neural circuits and synaptic plasticity. Our results indicate that decline in axons' ability to maintain complex regulatory networks may potentially play an important role in the increase in physiological dysregulation during aging.

Aim: Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods: Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results: Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion: Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.

The results of recent analyses showed that neuroinflammation—a key contributor to Alzheimer’s disease (AD)—is activated by protein complexes known as inflammasomes. The NLRP3 inflammasome protein complex is mostly studied in the central nervous system; it includes a protein encoded by the NLRP3 gene. Connections between inflammasomes, neuroinflammation, and AD may be regulated by small non-coding RNAs called microRNAs. These molecules have multiple ways to influence AD. For example, microRNA miR-107 may influence AD through regulation of the BACE1 gene expression involved in Aβ production. It remains unclear whether interplay of miR-107 and NRLP3 is associated with AD and whether mechanisms of such interplay differ among participants of LLFS and other studies. To address these questions, we evaluated associations with AD of interactions between genetic variants (SNPs) located in DNA encoding miR-107 and NLRP3 in participants of the LLFS and Framingham Heart Study using a logistic regression model with an interaction term. The facts that both datasets deal with data on related individuals and that many SNPs from either miR-107 or NLRP3 are in linkage disequilibrium were accounted for in these studies. The analysis of the Framingham data showed that the association with AD of the interaction between SNPs from miR-107 and the NLRP3 gene was statistically significant(p=6.71E-03; Bonferroni correction=7.14E-03). The association of the same interaction with AD was replicated in the analysis of LLFS data. These results indicate that in addition to regulating BACE1 expression and Aβ production, miR-107 may influence AD in interaction with the NLRP3 gene.

Genetics of aging is important since aging is a major risk factor in most diseases. Variables describing physiological state and cognitive functioning that influence morbidity and mortality risks can serve as biomarkers of aging. They change with increasing age and the ways in which these variables change can also influence these risks. Missing data due to dropout or death create problems in longitudinal studies producing biased results especially if the gap between exams is relatively long, as is the case in the Long Life Family Study (LLFS). We applied the threshold regression model to LLFS data to investigate the vitality and its rate, which are conceptualized as latent variables characterizing health and longevity, and to cope with such a problem. We performed genome-wide association study by sex and age groups to discover genetic signals on these phenotypes. We found 11 variants from the DACT2 gene, p-values < 1E-6 and variants rs12151399 (p-value = 8.43E-8, intron variant, gene AGAP1, in females), rs27958 (p-value = 8.39E-8, intron variant, gene ARHGAP26, in males) showing associations with the vitality. Olfactory receptors showed significant enrichment among the group of males over 80 years for the rate of aging phenotype. Results showed that vitality and its rate differ among sex and age groups. This work is an important step toward understanding the processes of aging linking the vitality with individual genetics using data from deceased and living individuals.

The lack of efficient medication against Alzheimer’s disease (AD) is the most important problem for this health disorder today. One possible reason for this -- the implementing medical interventions “too late in the disease stage” – has been recently addressed in the initiative that defined the preclinical AD stage by measuring changes in preclinical AD biomarkers. According to this definition, beta amyloid (Aβ) is one of the key preclinical AD biomarkers. Experimental studies showed that Aβ results from proteolytic cleavage of APP by β- and γ-secretases. Production of β-secretase involves BACE1 gene, activated by cellular stress response. This suggest that AD might be initiated by cellular stressors and that multifactorial regulation of AD is likely to be driven by genes involved in cellular stress response. In this paper we investigate whether interplay between SNPs from the EIF2AK4 gene involved in sensing cellular stress signals and the APP gene dealing with Aβ production may be associated with AD in human data. For this, we evaluated association of the interactions of the pairs of SNPs from these genes with AD in the analysis of HRS data. We found that interactions between several SNPs have statistically significant associations with AD. The results of this analysis confirm that the interplay between gene served as a sensor of cellular stress and gene involved in production of preclinical AD biomarker in response to stress may influence human AD. This analysis illustrates an important step towards translation of the results of experimental AD studies to human applications.

Aim Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Methods Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Results Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Conclusion Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.

Emerging evidence from experimental and clinical research suggests that stress-related genes may play key roles in AD development. The fact that genome-wide association studies were not able to detect a contribution of such genes to AD indicates the possibility that these genes may influence AD non-linearly, through interactions of their products. In this paper, we selected two stress-related genes (GCN2/EIF2AK4 and APP) based on recent findings from experimental studies which suggest that the interplay between these genes might influence AD in humans. To test this hypothesis, we evaluated the effects of interactions between SNPs in these two genes on AD occurrence, using the Health and Retirement Study data on white indidividuals. We found several interacting SNP-pairs whose associations with AD remained statistically significant after correction for multiple testing. These findings emphasize the importance of nonlinear mechanisms of polygenic AD regulation that cannot be detected in traditional association studies. To estimate collective effects of multiple interacting SNP-pairs on AD, we constructed a new composite index, called Interaction Polygenic Risk Score, and showed that its association with AD is highly statistically significant. These results open a new avenue in the analyses of mechanisms of complex multigenic AD regulation.

Biological aging results in changes in an organism that accumulate over age in a complex fashion across different regulatory systems, and their cumulative effect manifests in increased physiological dysregulation (PD) and declining robustness and resilience that increase risks of health disorders and death. Several composite measures involving multiple biomarkers that capture complex effects of aging have been proposed. We applied one such approach, the Mahalanobis distance (DM), to baseline measurements of various biomarkers (inflammation, hematological, diabetes-associated, lipids, endocrine, renal) in 3,279 participants from the Long Life Family Study (LLFS) with complete biomarker data. We used DM to estimate the level of PD by summarizing information about multiple deviations of biomarkers from specified “norms” in the reference population (here, LLFS participants younger than 60 years at baseline). An increase in DM was associated with significantly higher mortality risk (hazard ratio per standard deviation of DM: 1.42; 95% confidence interval: [1.3, 1.54]), even after adjustment for a composite measure summarizing 85 health-related deficits (disabilities, diseases, less severe symptoms), age, and other covariates. Such composite measures significantly improved mortality predictions especially in the subsample of participants from families enriched for exceptional longevity (the areas under the receiver operating characteristic curves are 0.88 vs. 0.85, in models with and without the composite measures, p = 2.9 × 10−5). Sensitivity analyses confirmed that our conclusions are not sensitive to different aspects of computational procedures. Our findings provide the first evidence of association of PD with mortality and its predictive performance in a unique sample selected for exceptional familial longevity.

Key Points Question Is leukocyte telomere length associated with the natural life span of contemporary humans? Findings This cohort study included 3259 participants from 3 longitudinal studies, of whom 1525 died during the follow-up period. Leukocyte telomere length–associated mortality from noncancer causes increased as participants aged, approaching their age at death. Meaning These data suggest that leukocyte telomere length is associated with a life span limit among contemporary humans., This cohort study examines whether leukocyte telomere length is associated with the life span of contemporary humans., Importance Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. Objective To examine whether LTL is associated with the life span of contemporary humans. Design, Setting, and Participants This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women’s Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Main Outcomes and Measures Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. Results The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). Conclusions and Relevance The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

Recently suggested novel implementation of the statistical distance measure (DM) for evaluating “physiological dysregulation” (PD) in aging individuals (based on measuring deviations of multiple biomarkers from baseline or normal physiological states) allows reducing high-dimensional biomarker space into a single PD estimate. Here we constructed DM using biomarker profiles from FRAMCOHORT (Framingham Heart Study) and CHS (Cardiovascular Health Study) Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center, and estimated effect of PD on total survival, onset of unhealthy life (proxy for “robustness”) and survival following the onset of unhealthy life (proxy for “resilience”). We investigated relationships between PD and declines in stress resistance and adaptive capacity not directly observed in data. PD was more strongly associated with the onset of unhealthy life than with survival after disease suggesting that declines in robustness and resilience with age may have overlapping as well as distinct mechanisms. We conclude that multiple deviations of physiological markers from their normal states (reflected in higher PD) may contribute to increased vulnerability to many diseases and precede their clinical manifestation. This supports potential use of PD in health care as a preclinical indicator of transition from healthy to unhealthy state.

A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection–free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection–free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection–free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis.

The special design of the Long Life Family Study provides a unique opportunity to investigate the genetics of human longevity by analyzing data on exceptional lifespans in families. In this article, we performed two series of genome wide association studies of human longevity which differed with respect to whether missing lifespan data were predicted or not predicted. We showed that the use of predicted lifespan is most beneficial when the follow-up period is relatively short. In addition to detection of strong associations of SNPs in APOE, TOMM40, NECTIN2, and APOC1 genes with longevity, we also detected a strong new association with longevity of rs1927465, located between the CYP26A1 and MYOF genes on chromosome 10. The association was confirmed using data from the Health and Retirement Study. We discuss the biological relevance of the detected SNPs to human longevity.

Our recent GWAS of a composite measure of physiological dysregulation (PD) in the Long Life Family Study (LLFS) found that the top genes associated with age-related changes in PD are involved in biological pathways relevant to maintaining neural networks and brain resilience. In our prior work, PD itself was linked to resilience-related traits. Alzheimer’s disease (AD) is a heterogeneous trait and it may involve an accelerated decline in resilience with age as a contributing factor. We proposed that genes associated with aging-changes in PD and brain resilience may contribute to AD risk. We investigated interactions between SNPs in such candidate genes with AD in LLFS and Health and Retirement Study (HRS). Our analysis revealed significant interactions between SNPs in UNC5C and other genes with AD, in both LLFS and HRS. These findings support roles of genetic interactions with UNC5C gene (implemented in axon growth and neuronal apoptosis) in AD.

Genetic risk factors for Alzheimer’s disease (AD) may facilitate AD-related changes in the brain long before AD clinical manifestation. While APOE4 was linked to a reduced hippocampal volume (HV) in a number of studies, the impact of rs2075650, another polymorphism strongly associated with AD, on HV is less clear. The rs2075650 (in TOMM40) is only in moderate to low LD with APOE4, and may have independent effects on HV or interact with APOE4. We studied associations of rs2075650 (G allele, risk factor for AD), rs429358 (C allele, proxy for APOE4), and their combinations, with right HV measured by MRI, among 10,738 women and 9,775 men aged 60-75, from UK Biobank. We found that right HV was significantly (p

Age-related phenotypes are characterized by genetic heterogeneity attributed to an uncertain role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic meta-analyses of 24 age-related phenotypes dealing with such evolutionary uncertainty and leveraging longitudinal information. Our analysis identified 237 novel single nucleotide polymorphisms (SNPs) in 199 loci with phenotype-specific (61 SNPs) and pleiotropic (176 SNPs) associations and replicated associations for 160 SNPs in 68 loci in a modest sample of 26,371 individuals from five longitudinal studies. Most pleiotropic associations (65.3%, 115 of 176 SNPs) were impacted by heterogeneity, with the natural-selection—free genetic heterogeneity as its inevitable component. This pleiotropic heterogeneity was dominated (93%, 107 of 115 SNPs) by antagonistic genetic heterogeneity, a phenomenon that is characterized by antagonistic directions of genetic effects for directly correlated phenotypes. Genetic association studies of age-related phenotypes addressing the evolutionary uncertainty in establishing their molecular mechanisms have power to substantially improve the efficiency of the analyses. A dominant form of heterogeneous pleiotropy, antagonistic genetic heterogeneity, provides unprecedented insight into the genetic origin of age-related phenotypes and side effects in medical care that is counter-intuitive in medical genetics but naturally expected when molecular mechanisms of age-related phenotypes are not due to direct evolutionary selection.

Summary Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age-related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age-related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high-density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large-scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10−30 for rs693 and β = −1.08, P = 9.8 × 10−42 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects—protecting against MI risks (β = −0.18, P = 1.1 × 10−5) or increasing MI risks (β = 0.15, P = 2.8 × 10−3) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10−8) that is contrasted with a weak estimate following the traditional, sample-size-centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.

BACKGROUNDS: Elucidating the causal effects of common intermediate risk factors on the onset of age-related diseases is indispensable for developing prevention and intervention procedures. METHODS: We conducted two-stage time-to-event Mendelian randomization meta-analyses combining five large-scale longitudinal cohorts to investigate the dynamic causal effects of cardiovascular disease risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-at-onset of age-related diseases. We constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. To examine potential pleiotropic effect, we also performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded to the survival context. RESULTS: Our results show that elevated BMI increases the absolute risk of type 2 diabetes (T2D) (p=7.68e-04), heart failure (p=9.03e-03), and cardiovascular diseases (CVD) (p=1.69e-03) and the effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses show that the association with stroke is attributed to the potential pleiotropic effects of rs2867125 and rs1558902 on BMI and stroke. Raised SBP levels are significantly associated with the development of atrial fibrillation (p=6.42e-03). Low-density lipoprotein cholesterol (LDL-C) levels are inversely associated with the age-at-onset of T2D (p=1.05e-02). In addition, LDL-C and triglycerides are inversely associated with the hazards of cancer and T2D, respectively. Nevertheless, the sensitivity analyses suggest that these associations are probably due to pleiotropic effects of several single-nucleotide polymorphisms including rs4970834 and rs1260326. CONCLUSIONS: Our results highlight the involvement of BMI in the development of multiple age-related diseases. We found that some observed causal associations can attribute to pleiotropic effects of some genetic variations. These findings have important implications in unraveling causal effects of common risk factors on age-related diseases and guiding effective intervention strategies to reduce the incidence of these 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.

Among age-specific diseases, Alzheimer’s disease (AD) is the most common type of disorder in the elderly populations. Recognizing genes involved in developing of AD using latest achievements of modern GWAS, statistical modeling and data management systems is among of the top priorities in modern human genetic studies.

The distance measure (DM) is a potential statistical approach to construct composite measures of physiological dysregulation based on multiple biomarkers. We constructed a DM using blood and other biomarker measures from two visits in the Long Life Family Study, with sex-specific means and variance-covariance matrices of individuals \lt;60 years at baseline representing the “reference” population. We found that an increase in DM is associated with higher mortality risk (HR=1.22; 95\% C.I.: [1.17, 1.27]), even after adjustment for a cumulative measure summarizing 85 deficits (disabilities, diseases, less severe symptoms). Our findings provide evidence that dynamics of DM represents an additional important predictor for mortality among older adults. We will discuss results of our ongoing genome-wide association studies of “static” (baseline value) and “dynamic” (slopes) characteristics of DM evaluated using joint models of longitudinal measurements of DM and mortality data which will illustrate genetic determinants of such measures.

Elucidating the causal effects of common intermediate phenotypes on the onset of age-related diseases such as cardiovascular diseases (CVD), diabetes mellitus (DM), Alzheimer’s disease and cancer is indispensable for developing prevention and intervention procedures. We conducted a Mendelian randomization study to investigate the causal effects of cardiovascular risk factors including body mass index (BMI), systolic blood pressure (SBP), and lipids on the age-of-onset of various age-related diseases using three large-scale longitudinal cohorts (ARIC, CHS and MESA). We performed a two-stage time-to-event analyses using additive hazard models followed by a meta-analysis using a fixed-effects model, in which we constructed weighted polygenic scores based on genetic markers from previously reported genome-wide association studies as instrumental variables to estimate the causal effects. Our results show that elevated BMI at the baseline increases the hazard of stroke with a meta-analysis p-value of 1.82e-02 (beta=3.11e-04, i.e., one unit increase of BMI is associated with 0.311 extra cases per 1,000 person years). Raised SBP significantly increases the hazards of coronary heart diseases (beta=3.66e-04, p=1.44e-03) and CVD (beta=4.17e-04, p=2.51e-02). We confirm that the association between low-density lipoprotein cholesterol and onset of Alzheimer’s disease is due to the pleiotropic effect in APOE. Surprisingly, we observe that triglycerides have a significant negative causal effect on the hazard of DM consistently across the three cohorts (beta=-1.88e-05, p=9.93e-03). These findings have important implications in guiding effective intervention strategies to reduce the incidence of these diseases.

Genetics of age-related diseases is complicated by the elusive role of evolution in fixing molecular mechanism of these phenotypes. This complexity implies an inherent genetic heterogeneity reflecting sensitivity of genetic associations to the life course. We used the results of a comprehensive analysis of genetic predisposition to 24 age-related phenotypes (16 biomarkers, 7 diseases, and death) in a modest sample (N=26,371) from five studies (ARIC, FHS, MESA, CHS, and CARDIA) from the Candidate Gene Association Resource, which leveraged this genetic heterogeneity. For bioinformatics analysis (IPA®) we selected 50 non-pleiotropic SNPs (mapped to 50 genes), which attained genome-wide significance with albumin in urine, and 122 pleiotropic SNPs (mapped to 99 genes), which attained genome-wide significance by combining statistics for 16 biomarkers. Five canonical pathways were genes enriched for non-pleiotropic SNPs at pBH

Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10−9), CHD by 35% (p = 8.9×10−6), HF by 55% (p = 9.7×10−5), stroke by 25% (p = 4.0×10−2), and ND by 100% (p = 1.3×10−3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10−21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality., Author Summary Biomedical research and medical care are traditionally focused on individual health conditions in order to postpone, ameliorate, or prevent the accumulation of morbidities in late life. An attractive idea is to find factors, which could reduce burden of not just one disease but a major subset of them to efficiently extend healthy lifespan. Here we focus on the analyses of genetic predisposition to risks of major human age-related diseases and mortality. The analyses highlight a locus in band 2q22.3 associated with risks of coronary heart disease, heart failure, stroke, diabetes, cancer, neurodegenerative diseases, and death. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.