Genetics of physiological dysregulation: Findings from the long life family study using joint models

Konstantin G. Arbeev, Olivia Bagley, Svetlana V. Ukraintseva, Deqing Wu, Hongzhe Duan, Alexander M. Kulminski, Eric Stallard, Kaare Christensen, Joseph H. Lee, Bharat Thyagarajan, Joseph M. Zmuda, Anatoliy I. Yashin

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish (US)
Pages (from-to)5920-5947
Number of pages28
JournalAging
Volume12
Issue number7
DOIs
StatePublished - Apr 15 2020

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health (NIA/NIH) under Award Numbers U01 AG023712 and U19AG063893. The work of K.G.A., O.B., S.V.U., D.W., H.D., A.M.K., E.S., and A.I.Y. was also partly supported by the NIA/NIH grant P01AG043352. The work of K.G.A., O.B., S.V.U., D.W., H.D., and A.I.Y. was also partly supported by the NIA/NIH grant R01AG062623. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© Arbeev et al.

Keywords

  • Aging
  • Joint models
  • Long life family study
  • Mahalanobis distance
  • Mortality

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