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

Recently, Mahalanobis distance (D _M ) was suggested as a statistical measure of physiological dysregulation in aging individuals. We constructed D _M 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 D _M and follow-up mortality in LLFS using joint models. We found that D _M 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 D _M 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 D _M constructed from biomarkers declining in late life. Review of biological effects of genes corresponding to top SNPs from GWAS of D _M 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.