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/759802525nas a2200313 4500008004100000022001400041245009700055210006900152260001500221300001200236490000700248520159500255653001001850653002601860653003101886653003401917653001301951653001101964653003601975100002802011700001602039700001602055700002602071700001902097700002102116700001502137700002302152856003602175 2018 eng d a1945-458900aStrong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes.0 aStrong impact of naturalselectionfree heterogeneity in genetics  c2018 03 29 a492-5140 v103 a

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.

10aAging10aComputational Biology10aGene Expression Regulation10aGenome-Wide Association Study10aGenotype10aHumans10aPolymorphism, Single Nucleotide1 aKulminski, Alexander, M1 aHuang, Jian1 aLoika, Yury1 aArbeev, Konstantin, G1 aBagley, Olivia1 aYashkin, Arseniy1 aDuan, Matt1 aCulminskaya, Irina uhttps://chs-nhlbi.org/node/825701508nas a2200253 4500008004100000022001400041245010400055210006900159260001600228520070900244100002600953700001500979700002300994700001901017700001901036700003001055700002401085700002101109700002301130700002101153700002101174700002301195856003601218 2023 eng d a1875-890800aVaccination Against Pneumonia May Provide Genotype-Specific Protection Against Alzheimer's Disease.0 aVaccination Against Pneumonia May Provide GenotypeSpecific Prote c2023 Oct 033 a

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.

1 aUkraintseva, Svetlana1 aDuan, Matt1 aSimanek, Amanda, M1 aHolmes, Rachel1 aBagley, Olivia1 aRajendrakumar, Aravind, L1 aYashkin, Arseniy, P1 aAkushevich, Igor1 aTropsha, Alexander1 aWhitson, Heather1 aYashin, Anatoliy1 aArbeev, Konstantin uhttps://chs-nhlbi.org/node/9509