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, ,

  • 1 Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham NC, 27708, USA
  • 2 Danish Aging Research Center, Department of Public Health, University of Southern Denmark 5000, Odense C, Denmark
  • 3 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA
  • 4 G. H. Sergievsky Center, Columbia University, New York, NY 10032, USA
  • 5 Departments of Epidemiology and Neurology, Columbia University Medical Center, New York, NY 10032, USA
  • 6 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA
  • 7 Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA 15261, USA

Received: October 11, 2019       Accepted: March 24, 2020       Published: April 1, 2020
How to Cite

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.


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.


AD: Alzheimer’s disease/dementia; CI: confidence interval; CVD: cardiovascular diseases; DM: the statistical (Mahalanobis) distance measure; FLoSS: Family Longevity Selection Score; GC: genomic control; GRM: genetic relationship matrix; GWAS: genome-wide association study; HR: hazard ratio; HWE: Hardy-Weinberg equilibrium; JM: joint model; LD: linkage disequilibrium; LLFS: Long Life Family Study; MAF: minor allele frequency; MNAR: missing not at random; PC: principal component; QC: quality control; RI: random intercept; RS: random slope; SD: standard deviation; SNP: single nucleotide polymorphism; SPM: stochastic process model.