Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging

Timmers, Paul R. H. J.; Tiys, Evgeny S.; Sakaue, Saori; Akiyama, Masato; Kiiskinen, Tuomo; Hwang, Shih‐Jen; Yao, Chen; Zhou, Wei; Deelen, Joris; Levy, Daniel L.; Ganna, Andrea; Kamatani, Yoichiro; Okada, Yukinori; Joshi, Peter K.; Wilson, James F.; Tsepilov, Yakov A.

doi:10.1038/s43587-021-00159-8

Cited by 28 publications

(22 citation statements)

References 79 publications

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“…Over the last few years, a lot of GWAS data have accumulated, even using alternative phenotypes (paternal longevity, health span, or some meta-analysis on these data), as described below. Six European-ancestry GWAS of human aging traits, i.e., health span, father and mother lifespan, exceptional longevity, frailty index, and self-rated health, have been combined in a principal component framework to maximize their shared genetic architecture [ 28 ]. In another study, authors have combined existing genome-wide association summary statistics for health span, parental lifespan, and longevity in a multivariate framework [ 29 ].…”

Section: Study Methodologiesmentioning

confidence: 99%

“…Other genes associated with blood lipid levels, inflammation, and immunity as well as the cardiovascular systems have also been suggested to contribute to longevity because they reduce the risk of heart disease, stroke, and insulin resistance. In addition, as suggested by the studies in mice, the pathways involved in nutrient-sensing signaling and in regulating transcription have been shown to be involved in modulating human longevity [ 28 , 29 , 30 , 60 , 61 , 62 ].…”

Section: Genes Shown To Be Associated With Longevitymentioning

confidence: 99%

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How Important Are Genes to Achieve Longevity?

Caruso

Ligotti

Accardi

et al. 2022

IJMS

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Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if any, as these studies pool together different populations. An alternative way might be the study of long-life families. This type of approach is proving to be an ideal resource for uncovering protective alleles and associated biological signatures for healthy aging phenotypes and exceptional longevity.

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Section: Study Methodologiesmentioning

confidence: 99%

Section: Genes Shown To Be Associated With Longevitymentioning

confidence: 99%

How Important Are Genes to Achieve Longevity?

Caruso

Ligotti

Accardi

et al. 2022

IJMS

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“…One of them is making a summary-level adjustment of traits by other traits using the same scheme as was used for obtaining the UGIT GWAS statistics. This can be helpful, for example, for ridding the studied trait’s genetic component of the genetic component that was caused by the confounding or unaccounted effects of assortative mating or family effects, which is quite a problem in GWAS at the biobank scale [ 15 , 23 ]. Another task is a GWAS for the trait that appears as a linear combination of the original traits.…”

Section: Discussionmentioning

confidence: 99%

“…This method is based on the calculation of the principal components using genetic rather than phenotypic correlations. We applied this method to genetically correlated pain phenotypes and aging related phenotypes and showed that the first GIP component, GIP1, that explains the largest proportion of the genetic variance probably could be interpreted as SGI [ 2 , 15 ]. This makes GIP promising for the identification of loci attributed to SGF.…”

Section: Introductionmentioning

confidence: 99%

A Novel Framework for Analysis of the Shared Genetic Background of Correlated Traits

Svishcheva

Tiys

Elgaeva

et al. 2022

Genes

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We propose a novel effective framework for the analysis of the shared genetic background for a set of genetically correlated traits using SNP-level GWAS summary statistics. This framework called SHAHER is based on the construction of a linear combination of traits by maximizing the proportion of its genetic variance explained by the shared genetic factors. SHAHER requires only full GWAS summary statistics and matrices of genetic and phenotypic correlations between traits as inputs. Our framework allows both shared and unshared genetic factors to be effectively analyzed. We tested our framework using simulation studies, compared it with previous developments, and assessed its performance using three real datasets: anthropometric traits, psychiatric conditions and lipid concentrations. SHAHER is versatile and applicable to summary statistics from GWASs with arbitrary sample sizes and sample overlaps, allows for the incorporation of different GWAS models (Cox, linear and logistic), and is computationally fast.

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“…Genes with consistent age effects on transcripts and proteins in kidney include Keg1 and Vcam1 (Figures 3D-E). VCAM1 is an immunoglobulin that facilitates interactions between vascular and immune cells and its increase with age has been associated with age-related disease in humans [20][21][22] . We observed increases in VCAM1 abundance with age across multiple tissues (kidney, liver, fat, and cerebellum), which resulted in a significant cross-tissue age effect (crosstissue age p = 1.59e-7).…”

Section: Most Age-related Changes In Protein Show No Corresponding Tr...mentioning

confidence: 99%

Global and tissue-specific aging effects on murine proteomes

Keele

Zhang

Szpyt

et al. 2022

Preprint

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Maintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional changes with age. We sought to define the effects of age directly at the protein level. We performed discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes at adult and late midlife ages (8 and 18 months). We find that sex differences in protein abundance align closely with previously collected transcriptomics data. However, aging changes are more prevalent in proteins and often have no corresponding transcriptional change. We observed increases in immune protein abundance across all tissues, consistent with immune infiltration with age. We also observed tissue-specific aging changes, including altered endoplasmic reticulum and protein trafficking protein abundances in the spleen, and altered stoichiometry in protein complexes related to proteostasis, such as the chaperonin-containing T-complex. This study provides a foundation for understanding systemic aging at the protein level.

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Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging

Cited by 28 publications

References 79 publications

How Important Are Genes to Achieve Longevity?

How Important Are Genes to Achieve Longevity?

A Novel Framework for Analysis of the Shared Genetic Background of Correlated Traits

Global and tissue-specific aging effects on murine proteomes

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