03411nas a2200289 4500008004100000022001400041245012400055210006900179260000900248300000800257490000600265520253800271100001402809700002402823700002302847700001602870700002602886700001702912700001902929700001502948700002102963700002902984700002003013700002403033700002803057856003603085 2016 eng d a1664-802100aPleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.0 aPleiotropic MetaAnalyses of Longitudinal Studies Discover Novel  c2016 a1790 v73 a

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 , rs460976 on 21q22.3 (1 kb from ) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in associated with stroke and heart failure, rs7081476 on 10p12.1 in 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.

1 aHe, Liang1 aKernogitski, Yelena1 aKulminskaya, Irina1 aLoika, Yury1 aArbeev, Konstantin, G1 aLoiko, Elena1 aBagley, Olivia1 aDuan, Matt1 aYashkin, Arseniy1 aUkraintseva, Svetlana, V1 aKovtun, Mikhail1 aYashin, Anatoliy, I1 aKulminski, Alexander, M uhttps://chs-nhlbi.org/node/856303045nas a2200205 4500008004100000022001400041245013700055210006900192260001600261520236100277100001402638700002302652700001602675700002602691700001902717700001502736700002402751700002802775856003602803 2017 eng d a1873-681500aCausal effects of cardiovascular risk factors on onset of major age-related diseases: A time-to-event Mendelian randomization study.0 aCausal effects of cardiovascular risk factors on onset of major  c2017 Sep 283 a

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.

1 aHe, Liang1 aCulminskaya, Irina1 aLoika, Yury1 aArbeev, Konstantin, G1 aBagley, Olivia1 aDuan, Matt1 aYashin, Anatoliy, I1 aKulminski, Alexander, M uhttps://chs-nhlbi.org/node/766502910nas a2200265 4500008004100000022001400041245011100055210006900166260001600235520208900251100002402340700001502364700002002379700001502399700001502414700002302429700002102452700002502473700002302498700002102521700002102542700001902563700002602582856003602608 2017 eng d a1873-681500aHidden heterogeneity in Alzheimer's disease: Insights from genetic association studies and other analyses.0 aHidden heterogeneity in Alzheimers disease Insights from genetic c2017 Oct 263 a

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection.

1 aYashin, Anatoliy, I1 aFang, Fang1 aKovtun, Mikhail1 aWu, Deqing1 aDuan, Matt1 aArbeev, Konstantin1 aAkushevich, Igor1 aKulminski, Alexander1 aCulminskaya, Irina1 aZhbannikov, Ilya1 aYashkin, Arseniy1 aStallard, Eric1 aUkraintseva, Svetlana uhttps://chs-nhlbi.org/node/759802054nas a2200481 4500008004100000022001400041245005600055210005500111260001300166300001400179490000600193520069800199100002300897700002000920700002000940700002300960700002600983700002401009700002301033700002301056700002101079700002401100700001901124700002101143700002201164700001801186700002101204700002001225700001701245700002001262700002801282700001401310700002401324700002701348700002301375700002501398700002201423700002301445700002401468700002601492700001801518856003601536 2017 eng d a1945-458900aTelomeres and the natural lifespan limit in humans.0 aTelomeres and the natural lifespan limit in humans c2017 Apr a1130-11420 v93 a

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

1 aSteenstrup, Troels1 aKark, Jeremy, D1 aVerhulst, Simon1 aThinggaard, Mikael1 aHjelmborg, Jacob, V B1 aDalgÄrd, Christine1 aKyvik, Kirsten Ohm1 aChristiansen, Lene1 aMangino, Massimo1 aSpector, Timothy, D1 aPetersen, Inge1 aKimura, Masayuki1 aBenetos, Athanase1 aLabat, Carlos1 aSinnreich, Ronit1 aHwang, Shih-Jen1 aLevy, Daniel1 aHunt, Steven, C1 aFitzpatrick, Annette, L1 aChen, Wei1 aBerenson, Gerald, S1 aBarbieri, Michelangela1 aPaolisso, Giuseppe1 aGadalla, Shahinaz, M1 aSavage, Sharon, A1 aChristensen, Kaare1 aYashin, Anatoliy, I1 aArbeev, Konstantin, G1 aAviv, Abraham uhttps://chs-nhlbi.org/node/759102929nas a2200289 4500008004100000022001400041245011200055210006900167260001600236300001200252490000600264520204600270100002602316700002002342700002302362700002002385700001902405700002402424700002502448700002002473700001702493700002802510700002302538700002402561700001802585856003602603 2020 eng d a2574-380500aAssociation of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.0 aAssociation of Leukocyte Telomere Length With Mortality Among Ad c2020 Feb 05 ae2000230 v33 a

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.

1 aArbeev, Konstantin, G1 aVerhulst, Simon1 aSteenstrup, Troels1 aKark, Jeremy, D1 aBagley, Olivia1 aKooperberg, Charles1 aReiner, Alexander, P1 aHwang, Shih-Jen1 aLevy, Daniel1 aFitzpatrick, Annette, L1 aChristensen, Kaare1 aYashin, Anatoliy, I1 aAviv, Abraham uhttps://chs-nhlbi.org/node/8282