Aging
Navigate
Submit an Article
Research Paper|Volume 12, Issue 7|pp 5920—5947

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

Konstantin G. Arbeev1, Olivia Bagley1, Svetlana V. Ukraintseva1, Deqing Wu1, Hongzhe Duan1, Alexander M. Kulminski1, Eric Stallard1, Kaare Christensen2, Joseph H. Lee3,4,5, Bharat Thyagarajan6, Joseph M. Zmuda7, Anatoliy I. Yashin1
  • 1Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham NC, 27708, USA
  • 2Danish Aging Research Center, Department of Public Health, University of Southern Denmark 5000, Odense C, Denmark
  • 3Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA
  • 4G. H. Sergievsky Center, Columbia University, New York, NY 10032, USA
  • 5Departments of Epidemiology and Neurology, Columbia University Medical Center, New York, NY 10032, USA
  • 6Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
  • 7Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
Received: October 11, 2019Accepted: March 24, 2020Published: April 1, 2020
https://doi.org/10.18632/aging.102987

Copyright © 2020 Arbeev et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.