31 results on '"Bagley O"'
Search Results
2. APPLICATIONS OF GENETIC STOCHASTIC PROCESS MODEL IN STUDIES OF DEVELOPMENT OF ALZHEIMER’S DISEASE
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Zhbannikov, I.Y., primary, Arbeev, K., additional, Bagley, O., additional, Duan, M., additional, Yashin, A.I., additional, and Ukraintseva, S.V., additional
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- 2017
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3. ESTIMATION OF CAUSAL EFFECTS ON HAZARDS OF MAJOR AGE-RELATED DISEASES USING MENDELIAN RANDOMIZATION
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He, L., primary, Culminskaya, I., additional, Loika, Y., additional, Arbeev, K., additional, Bagley, O., additional, Yashin, A.I., additional, and Kulminski, A., additional
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- 2017
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4. PATHWAYS ENRICHMENT AND AGE-RELATED PHENOTYPES: NON-PLEIOTROPIC SNPS VERSUS PLEIOTROPIC SNPS
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Kulminskaya, I., primary, Loika, Y., additional, Huang, J., additional, Arbeev, K., additional, Bagley, O., additional, Yashin, A.I., additional, and Kulminski, A., additional
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- 2017
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5. APOE4 and Infectious Diseases Jointly Contribute to Brain Glucose Hypometabolism, a Biomarker of Alzheimer's Pathology: New findings from the ADNI.
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Rajendrakumar AL, Arbeev KG, Bagley O, Yashin AI, and Ukraintseva S
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Introduction: We investigated the interplay between infections and APOE4 on brain glucose hypometabolism, an early preclinical feature of Alzheimer's Disease (AD) pathology., Methods: Multivariate linear regression analysis was performed on 1,509 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The outcomes were the rank-normalized hypometabolic convergence index (HCI) and statistical regions of interest (SROI) for AD and mild cognitive impairment (MCI). Further, the HCI and its change in the presence and absence of APOE4 were evaluated., Results: Infections were associated with greater hypometabolism [0.15, 95% CI: 0.03, 0.27, p=0.01], with a more pronounced effect among APOE4 carriers, indicating an interaction effect. A higher HCI (0.44, p=0.01) was observed in APOE4 carriers with multiple infections, compared to (0.11, p=0.08) for those with a single infection, revealing a dose-response relationship. The corresponding estimates for the association of infections with SROI AD and SROI MCI were -0.01 (p=0.02) and -0.01 (p=0.04) respectively., Conclusion: Our findings suggest that infections and APOE4 jointly contribute to brain glucose hypometabolism and AD pathology, supporting a "multi-hit" mechanism in AD development., Competing Interests: Competing Interests The authors declare no competing interests.
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- 2024
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6. The association between rs6859 in NECTIN2 gene and Alzheimer's disease is partly mediated by pTau.
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Rajendrakumar AL, Arbeev KG, Bagley O, Yashin AI, and Ukraintseva S
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Introduction: Emerging evidence suggests a connection between vulnerability to infections and Alzheimer's disease (AD). The nectin cell adhesion molecule 2 (NECTIN2) gene coding for a membrane component of adherens junctions is involved in response to infections, and its single nucleotide polymorphism (SNP) rs6859 was significantly associated with AD risk in several human cohorts. It is unclear, however, how exactly rs6859 influences the development of AD pathology. The aggregation of hyperphosphorylated tau protein (pTau) is a key pathological feature of neurodegeneration in AD, which may be induced by infections, among other factors, and potentially influenced by genes involved in both AD and vulnerability to infections, such as NECTIN2 ., Materials and Methods: We conducted a causal mediation analysis (CMA) on a sample of 708 participants in the Alzheimer's disease Neuroimaging Initiative (ADNI). The relationship between rs6859 and Alzheimer's disease (AD), with AD (yes/no) as the outcome and pTau-181 levels in the cerebrospinal fluid (CSF) acting as a mediator in this association, was assessed. Adjusted estimates from the probit and linear regression models were used in the CMA model, where an additive model considered an increase in dosage of the rs6859 A allele (AD risk factor)., Results: The increase in dose of allele A of the SNP rs6859 resulted in about 0.144 increase per standard deviation (SD) of pTau-181 (95% CI: 0.041, 0.248, p < 0.01). When included together in the probit model, the change in A allele dose and each standard deviation change in pTau-181 predicted 6.84% and 9.79% higher probabilities for AD, respectively. In the CMA, the proportion of the average mediated effect was 17.05% and was higher for the risk allele homozygotes (AA), at 19.40% (95% CI: 6.20%, 43.00%, p < 0.01). The sensitivity analysis confirmed the evidence of a robust mediation effect., Conclusion: This study reported a new potential causal relationship between pTau-181 and AD. We found that the association between rs6859 in the NECTIN2 gene and AD is partly mediated by pTau-181 levels in CSF. The rest of this association may be mediated by other factors. Our finding sheds light on the complex interplay between genetic susceptibility, protein aggregation, and neurodegeneration in AD. Further research, using other biomarkers, is needed to uncover the remaining mechanisms of the association between the NECTIN2 gene and AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rajendrakumar, Arbeev, Bagley, Yashin and Ukraintseva.)
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- 2024
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7. Methods for joint modelling of longitudinal omics data and time-to-event outcomes: Applications to lysophosphatidylcholines in connection to aging and mortality in the Long Life Family Study.
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Arbeev KG, Bagley O, Ukraintseva SV, Kulminski A, Stallard E, Schwaiger-Haber M, Patti GJ, Gu Y, Yashin AI, and Province MA
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Studying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases., Competing Interests: CONFLICT OF INTEREST The authors declare no conflicts of interest related to this study.
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- 2024
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8. Overweight as a Causal Factor Contributing to Better Survival at the Oldest Old Ages: A Mendelian Randomization Study.
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Duan H, Arbeev K, Holmes R, Bagley O, Wu D, Akushevich I, Schupf N, Yashin A, and Ukraintseva S
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Overweight, defined by a body mass index (BMI) between 25 and 30, has been associated with enhanced survival among older adults in some studies. However, whether being overweight is causally linked to longevity remains unclear. To investigate this, we conducted a Mendelian randomization (MR) study of lifespan 85+ years, using overweight as an exposure variable and data from the Health and Retirement Study and the Long Life Family Study. An essential aspect of MR involves selecting appropriate single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). This is challenging due to the limited number of SNP candidates within biologically relevant genes that can satisfy all necessary assumptions and criteria. To address this challenge, we employed a novel strategy of creating additional IVs by pairing SNPs between candidate genes. This strategy allowed us to expand the pool of IV candidates with new 'composite' SNPs derived from eight candidate obesity genes. Our study found that being overweight between ages 75 and 85, compared to having a normal weight (BMI 18.5-24.9), significantly contributes to improved survival beyond age 85. Results of this MR study thus support a causal relationship between overweight and longevity in older adults., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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- 2024
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9. How are APOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis.
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Holmes R, Duan H, Bagley O, Wu D, Loika Y, Kulminski A, Yashin A, Arbeev K, and Ukraintseva S
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The ε4 allele of the APOE gene ( APOE4 ) is known for its negative association with human longevity; however, the mechanism is unclear. APOE4 is also linked to changes in body weight, and the latter changes were associated with survival in some studies. Here, we explore the role of aging changes in weight in the connection between APOE4 and longevity using the causal mediation analysis (CMA) approach to uncover the mechanisms of genetic associations. Using the Health and Retirement Study (HRS) data, we tested a hypothesis of whether the association of APOE4 with reduced survival to age 85+ is mediated by key characteristics of age trajectories of weight, such as the age at reaching peak values and the slope of the decline in weight afterward. Mediation effects were evaluated by the total effect (TE), natural indirect effect, and percentage mediated. The controlled direct effect and natural direct effect are also reported. The CMA results suggest that APOE4 carriers have 19%-22% (TE p = 0.020-0.039) lower chances of surviving to age 85 and beyond, in part, because they reach peak values of weight at younger ages, and their weight declines faster afterward compared to non-carriers. This finding is in line with the idea that the detrimental effect of APOE4 on longevity is, in part, related to the accelerated physical aging of ε4 carriers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Holmes, Duan, Bagley, Wu, Loika, Kulminski, Yashin, Arbeev and Ukraintseva.)
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- 2024
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10. The SNP rs6859 in NECTIN2 gene is associated with underlying heterogeneous trajectories of cognitive changes in older adults.
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Rajendrakumar AL, Arbeev KG, Bagley O, Yashin AI, and Ukraintseva S
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- Aged, Humans, Cognition, Cross-Sectional Studies, Retrospective Studies, Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Cognitive Dysfunction diagnosis
- Abstract
Background: Functional decline associated with dementia, including in Alzheimer's disease (AD), is not uniform across individuals, and respective heterogeneity is not yet fully explained. Such heterogeneity may in part be related to genetic variability among individuals. In this study, we investigated whether the SNP rs6859 in nectin cell adhesion molecule 2 (NECTIN2) gene (a major risk factor for AD) influences trajectories of cognitive decline in older participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI)., Methods: We retrospectively analyzed records on 1310 participants from the ADNI database for the multivariate analysis. We used longitudinal measures of Mini-Mental State Examination (MMSE) scores in participants, who were cognitively normal, or having AD, or other cognitive deficits to investigate the trajectories of cognitive changes. Multiple linear regression, linear mixed models and latent class analyses were conducted to investigate the association of the SNP rs6859 with MMSE., Results: The regression coefficient per one allele dose of the SNP rs6859 was independently associated with MMSE in both cross-sectional (-2.23, p < 0.01) and linear mixed models (-2.26, p < 0.01) analyses. The latent class model with three distinct subgroups (class 1: stable and gradual decline, class 2: intermediate and late decline, and class 3: lowest and irregular) performed best in the posterior classification, 42.67% (n = 559), 21.45% (n = 281), 35.88% (n = 470) were classified as class 1, class 2, and class 3. In the heterogeneous linear mixed model, the regression coefficient per one allele dose of rs6859 - A risk allele was significantly associated with MMSE class 1 and class 2 memberships and related decline; Class 1 (-2.28, 95% CI: -4.05, -0.50, p < 0.05), Class 2 (-5.56, 95% CI: -9.61, -1.51, p < 0.01) and Class 3 (-0.37, 95% CI: -1.62, 0.87, p = 0.55)., Conclusions: This study found statistical evidence supporting the classification of three latent subclass groups representing complex MMSE trajectories in the ADNI cohort. The SNP rs6859 can be suggested as a candidate genetic predictor of variation in modeling MMSE trajectory, as well as for identifying latent classes with higher baseline MMSE. Functional studies may help further elucidate this relationship., (© 2024. The Author(s).)
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- 2024
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11. Patterns of Aging Changes in Bodyweight May Predict Alzheimer's Disease.
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Ukraintseva S, Duan H, Holmes R, Bagley O, Wu D, Yashkin A, Kulminski A, Akushevich I, Whitson H, Stallard E, Yashin A, and Arbeev K
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- Humans, Female, Aging, Apolipoprotein E4 genetics, Alzheimer Disease
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Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated physical aging contributing to AD.
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- 2024
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12. Interactions between genes involved in physiological dysregulation and axon guidance: role in Alzheimer's disease.
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Arbeev KG, Ukraintseva S, Bagley O, Duan H, Wu D, Akushevich I, Stallard E, Kulminski A, Christensen K, Feitosa MF, O'Connell JR, Parker D, Whitson H, and Yashin AI
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Dysregulation of physiological processes may contribute to Alzheimer's disease (AD) development. We previously found that an increase in the level of physiological dysregulation (PD) in the aging body is associated with declining resilience and robustness to major diseases. Also, our genome-wide association study found that genes associated with the age-related increase in PD frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration) in the literature. Here, we tested the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We assessed the impact of interactions between SNPs in such genes on AD onset in the Long Life Family Study and sought to replicate the findings in the Health and Retirement Study. We found significant interactions between SNPs in the UNC5C and CNTN6 , and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Associations with individual SNPs were not statistically significant. Our findings, thus, support a major role of genetic interactions in the heterogeneity of AD and suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Arbeev, Ukraintseva, Bagley, Duan, Wu, Akushevich, Stallard, Kulminski, Christensen, Feitosa, O’Connell, Parker, Whitson and Yashin.)
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- 2023
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13. Understanding Alzheimer's disease in the context of aging: Findings from applications of stochastic process models to the Health and Retirement Study.
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Arbeev KG, Bagley O, Yashkin AP, Duan H, Akushevich I, Ukraintseva SV, and Yashin AI
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- Aged, United States epidemiology, Humans, Retirement, Medicare, Aging, Apolipoproteins E genetics, Alzheimer Disease epidemiology, Alzheimer Disease genetics
- Abstract
There is growing literature on applications of biodemographic models, including stochastic process models (SPM), to studying regularities of age dynamics of biological variables in relation to aging and disease development. Alzheimer's disease (AD) is especially good candidate for SPM applications because age is a major risk factor for this heterogeneous complex trait. However, such applications are largely lacking. This paper starts filling this gap and applies SPM to data on onset of AD and longitudinal trajectories of body mass index (BMI) constructed from the Health and Retirement Study surveys and Medicare-linked data. We found that APOE e4 carriers are less robust to deviations of trajectories of BMI from the optimal levels compared to non-carriers. We also observed age-related decline in adaptive response (resilience) related to deviations of BMI from optimal levels as well as APOE- and age-dependence in other components related to variability of BMI around the mean allostatic values and accumulation of allostatic load. SPM applications thus allow revealing novel connections between age, genetic factors and longitudinal trajectories of risk factors in the context of AD and aging creating new opportunities for understanding AD development, forecasting trends in AD incidence and prevalence in populations, and studying disparities in those., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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14. Vaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease.
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Ukraintseva S, Duan M, Simanek AM, Holmes R, Bagley O, Rajendrakumar AL, Yashkin AP, Akushevich I, Tropsha A, Whitson H, Yashin A, and Arbeev K
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- Humans, Aged, Retrospective Studies, Vaccination, Pneumococcal Vaccines therapeutic use, Genotype, Pneumonia, Pneumococcal prevention & control, Alzheimer Disease genetics, Alzheimer Disease prevention & control
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Vaccine repurposing that considers individual genotype may aid personalized prevention of Alzheimer's disease (AD). In this retrospective cohort study, we used Cardiovascular Health Study data to estimate associations of pneumococcal polysaccharide vaccine and flu shots received between ages 65-75 with AD onset at age 75 or older, taking into account rs6859 polymorphism in NECTIN2 gene (AD risk factor). Pneumococcal vaccine, and total count of vaccinations against pneumonia and flu, were associated with lower odds of AD in carriers of rs6859 A allele, but not in non-carriers. We conclude that pneumococcal polysaccharide vaccine is a promising candidate for genotype-tailored AD prevention.
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- 2023
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15. APOE ɛ4 allele and TOMM40-APOC1 variants jointly contribute to survival to older ages.
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Kulminski AM, Jain-Washburn E, Philipp I, He L, Loika Y, Loiko E, Bagley O, Ukraintseva S, Yashin A, Arbeev K, Stallard E, Feitosa MF, Schupf N, Christensen K, and Culminskaya I
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- Humans, Middle Aged, Aged, Alleles, Genotype, Heterozygote, Apolipoprotein E4 genetics, Mitochondrial Precursor Protein Import Complex Proteins, Apolipoproteins E genetics, Alzheimer Disease genetics
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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., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
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- 2022
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16. Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation.
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Ukraintseva S, Duan M, Arbeev K, Wu D, Bagley O, Yashkin AP, Gorbunova G, Akushevich I, Kulminski A, and Yashin A
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A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging - changes in the body and extend limits of human lifespan. However, majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene-environment and gene-gene interactions, among other factors. In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant (FDR < 0.05) effects of interactions between SNPs in IGF1R , TGFBR2 , and BCL2 on survival 85+. We validated these findings in the Cardiovascular Health Study sample, with P < 0.05, using survival to age 85+, and to the 90th percentile, as outcomes. Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ukraintseva, Duan, Arbeev, Wu, Bagley, Yashkin, Gorbunova, Akushevich, Kulminski and Yashin.)
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- 2021
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17. Interplay between stress-related genes may influence Alzheimer's disease development: The results of genetic interaction analyses of human data.
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Yashin AI, Wu D, Arbeev K, Bagley O, Akushevich I, Duan M, Yashkin A, and Ukraintseva S
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- Humans, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Risk Factors, Alzheimer Disease genetics, Amyloid beta-Protein Precursor genetics, Epistasis, Genetic genetics, Protein Serine-Threonine Kinases genetics
- Abstract
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., (Copyright © 2021. Published by Elsevier B.V.)
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- 2021
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18. Roles of interacting stress-related genes in lifespan regulation: insights for translating experimental findings to humans.
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Yashin AI, Wu D, Arbeev K, Yashkin AP, Akushevich I, Bagley O, Duan M, and Ukraintseva S
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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., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.
- Published
- 2021
19. Genetics of physiological dysregulation: findings from the long life family study using joint models.
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Arbeev KG, Bagley O, Ukraintseva SV, Wu D, Duan H, Kulminski AM, Stallard E, Christensen K, Lee JH, Thyagarajan B, Zmuda JM, and Yashin AI
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- Biomarkers analysis, Female, Gene Regulatory Networks, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors genetics, Humans, Joints physiology, Joints physiopathology, Longitudinal Studies, Male, Models, Biological, Mortality, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases genetics, Aging genetics, Aging physiology, Chronobiology Phenomena genetics, Neoplasms diagnosis, Neoplasms genetics, Neural Pathways physiology, Neuronal Plasticity genetics
- Abstract
Recently, Mahalanobis distance (D
M ) 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.- Published
- 2020
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20. Composite Measure of Physiological Dysregulation as a Predictor of Mortality: The Long Life Family Study.
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Arbeev KG, Bagley O, Ukraintseva SV, Duan H, Kulminski AM, Stallard E, Wu D, Christensen K, Feitosa MF, Thyagarajan B, Zmuda JM, and Yashin AI
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- Biomarkers, Humans, Proportional Hazards Models, ROC Curve, Aging, Longevity
- Abstract
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 (D
M ), 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., (Copyright © 2020 Arbeev, Bagley, Ukraintseva, Duan, Kulminski, Stallard, Wu, Christensen, Feitosa, Thyagarajan, Zmuda and Yashin.)- Published
- 2020
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21. Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.
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Arbeev KG, Verhulst S, Steenstrup T, Kark JD, Bagley O, Kooperberg C, Reiner AP, Hwang SJ, Levy D, Fitzpatrick AL, Christensen K, Yashin AI, and Aviv A
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- Aged, Aged, 80 and over, Cardiovascular Diseases mortality, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neoplasms mortality, Leukocytes physiology, Life Expectancy, Telomere genetics
- Abstract
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.
- Published
- 2020
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22. Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms.
- Author
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Kulminski AM, Loika Y, Huang J, Arbeev KG, Bagley O, Ukraintseva S, Yashin AI, and Culminskaya I
- Abstract
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.
- Published
- 2019
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23. "Physiological Dysregulation" as a Promising Measure of Robustness and Resilience in Studies of Aging and a New Indicator of Preclinical Disease.
- Author
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Arbeev KG, Ukraintseva SV, Bagley O, Zhbannikov IY, Cohen AA, Kulminski AM, and Yashin AI
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Female, Humans, Longitudinal Studies, Male, Middle Aged, Proportional Hazards Models, United States, Adaptation, Physiological physiology, Aging physiology, Health Status
- Abstract
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., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.)
- Published
- 2019
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24. Independent associations of TOMM40 and APOE variants with body mass index.
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Kulminski AM, Loika Y, Culminskaya I, Huang J, Arbeev KG, Bagley O, Feitosa MF, Zmuda JM, Christensen K, and Yashin AI
- Subjects
- Adult, Aged, Aged, 80 and over, Aging genetics, Cohort Studies, Genotype, Humans, Linkage Disequilibrium genetics, Middle Aged, Mitochondrial Precursor Protein Import Complex Proteins, Multivariate Analysis, Apolipoproteins E genetics, Body Mass Index, Genetic Association Studies, Membrane Transport Proteins genetics, Polymorphism, Single Nucleotide genetics
- Abstract
The TOMM40-APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40-APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age-aggregated and age-stratified cohort-specific and cohort-pooled analysis of 27,863 Caucasians aged 20-100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = -1.29, p = 3.97 × 10
-9 ; β = -1.38, p = 2.78 × 10-10 ; and β = 0.58, p = 3.04 × 10-2 , respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI-lowering associations for minor alleles (β = -0.63, p = 3.99 × 10-2 and β = -0.94, p = 2.17 × 10-3 , respectively). Polygenic mega-analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = -1.68, p = 3.00 × 10-9 ), and the strongest BMI-lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = -4.11, p = 2.78 × 10-3 ). Conditional analysis with four polymorphisms identified independent BMI-lowering (rs2075650, rs157580, and rs429358) and BMI-increasing (rs7412) associations of heterozygous genotypes with BMI. Age-stratified conditional analysis revealed well-powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = -1.18, 2.35, p = 5.18 × 10-1 for 3,068 individuals aged ≤30 years and β = -4.28, CI = -5.65, -2.92, p = 7.71 × 10-10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4-coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals., (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2019
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25. Genetics of Human Longevity From Incomplete Data: New Findings From the Long Life Family Study.
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Yashin AI, Arbeev KG, Wu D, Arbeeva LS, Bagley O, Stallard E, Kulminski AM, Akushevich I, Fang F, Wojczynski MK, Christensen K, Newman AB, Boudreau RM, Province MA, Thielke S, Perls TT, An P, Elo I, and Ukraintseva SV
- Subjects
- Aged, Aged, 80 and over, Apolipoprotein C-I genetics, Apolipoproteins E genetics, Calcium-Binding Proteins genetics, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 19, Denmark, Female, Gene Frequency, Genome-Wide Association Study, Humans, Logistic Models, Longitudinal Studies, Male, Membrane Proteins genetics, Membrane Transport Proteins, Mitochondrial Precursor Protein Import Complex Proteins, Muscle Proteins genetics, Nectins, Retinoic Acid 4-Hydroxylase genetics, United States, Longevity genetics, Pedigree, Polymorphism, Single Nucleotide
- Abstract
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.
- Published
- 2018
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26. Causal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study.
- Author
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He L, Culminskaya I, Loika Y, Arbeev KG, Bagley O, Duan M, Yashin AI, and Kulminski AM
- Subjects
- Blood Pressure, Body Mass Index, Cholesterol, HDL blood, Cholesterol, LDL blood, Female, Genetic Variation, Genome-Wide Association Study, Humans, Linear Models, Longitudinal Studies, Male, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides blood, Aging, Cardiovascular Diseases genetics, Causality, Diabetes Mellitus, Type 2 genetics, Neoplasms genetics, Stroke genetics
- Abstract
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 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 avoid false positive due to potential pleiotropic effects of the genetic markers, we performed a leave-one-out sensitivity analysis and an MR-Egger sensitivity analysis that we expanded in 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 causal effects start at different ages. A significant association between BMI and the risk of stroke is observed; however, the sensitivity analyses suggest that the association is attributed to the potential pleiotropic effects of rs2867125 and rs1558902. 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 risks 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. 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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27. Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.
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Kulminski AM, Huang J, Loika Y, Arbeev KG, Bagley O, Yashkin A, Duan M, and Culminskaya I
- Subjects
- Computational Biology, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Aging genetics, Aging physiology, Gene Expression Regulation physiology
- Abstract
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.
- Published
- 2018
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28. Corrigendum: Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
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He L, Kernogitski Y, Kulminskaya I, Loika Y, Arbeev KG, Loiko E, Bagley O, Duan M, Yashkin A, Ukraintseva SV, Kovtun M, Yashin AI, and Kulminski AM
- Abstract
[This corrects the article on p. 179 in vol. 7, PMID: 27790247.].
- Published
- 2018
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29. Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.
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Kulminski AM, Kernogitski Y, Culminskaya I, Loika Y, Arbeev KG, Bagley O, Duan M, Arbeeva L, Ukraintseva SV, Wu D, Stallard E, and Yashin AI
- Subjects
- Adolescent, Adult, Aged, 80 and over, Child, Child, Preschool, Humans, Middle Aged, Myocardial Infarction mortality, Polymorphism, Single Nucleotide genetics, Risk Factors, Young Adult, Alleles, Apolipoproteins B genetics, Endophenotypes metabolism, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Heart physiopathology, Myocardial Infarction genetics
- Abstract
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., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2017
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30. Pleiotropic Associations of Allelic Variants in a 2q22 Region with Risks of Major Human Diseases and Mortality.
- Author
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Kulminski AM, He L, Culminskaya I, Loika Y, Kernogitski Y, Arbeev KG, Loiko E, Arbeeva L, Bagley O, Duan M, Yashkin A, Fang F, Kovtun M, Ukraintseva SV, Wu D, and Yashin AI
- Subjects
- Atherosclerosis genetics, Atherosclerosis mortality, Chromosomes, Human, Pair 2 genetics, Coronary Disease genetics, Coronary Disease mortality, Diabetes Mellitus genetics, Diabetes Mellitus mortality, Female, Genetic Association Studies, Genetic Diseases, Inborn mortality, Genetic Pleiotropy, Genetic Predisposition to Disease, Heart Failure genetics, Heart Failure mortality, Humans, Male, Risk Factors, Stroke genetics, Stroke mortality, Zinc Finger E-box Binding Homeobox 2, Activin Receptors, Type II genetics, Genetic Diseases, Inborn genetics, Genome-Wide Association Study, Homeodomain Proteins genetics, Repressor Proteins genetics
- Abstract
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., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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31. Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
- Author
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He L, Kernogitski Y, Kulminskaya I, Loika Y, Arbeev KG, Loiko E, Bagley O, Duan M, Yashkin A, Ukraintseva SV, Kovtun M, Yashin AI, and Kulminski AM
- Abstract
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.
- Published
- 2016
- Full Text
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