¹National Health Research Institutes, Center for Neuropsychiatric Research, Miaoli County, Taiwan, ²Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang Gung University, Department of Neurology, Taoyuan, Taiwan, ³Taoyuan Chang Gung Memorial Hospital, Dementia Center, Taoyuan, Taiwan, ⁴National Health Research Institutes, Institute of Population Health Sciences, Miaoli County, Taiwan, ⁵National Health Research Institutes, National Center for Geriatrics and Welfare Research, YunlinT, Taiwan, ⁶National Health Research Institutes, Institute of Molecular and Genomic Medicine, Miaoli County, Taiwan, ⁷National Yang Ming Chiao Tung University, Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan, ⁸China Medical University, Ph.D. Program for Aging, Taichung, Taiwan

Background: Frailty is a medical condition commonly observed in older adults, characterized by declines in physical, mental, and social functions. In this study, we focus on the physical aspects of frailty, which include five components: unintentional weight loss, exhaustion, low physical activity, slow walking speed, and weak grip strength. The total score derived from these components was analyzed genome-wide using data from the Healthy Aging Longitudinal Study (HALST). This study tested the hypothesis of candidate gene associations with the total score of frailty (TSF). Mental status was assessed using the Mini-Mental State Examination (MMSE) to evaluate cognitive function, and an objective neuroinjury biomarker, neurofilament light chain (NfL), was used to detect alterations in neuronal function.

Aims & Objectives: This study aims to identify candidate genes associated with the TSF and their missense alterations to assess their role in the mechanisms of physical decline.

Method: A genome-wide association study (GWAS) was conducted on TSF from Wave 2 (average age 66) of HALST, involving 288 participants. The TSF was calculated as the sum of five components. Gene-based p-values were computed to identify significant genetic loci. Differences in frailty scores across rs2288538 genotypes were compared between age 60 (Wave 1) and age 66 (Wave 2) in the same healthy participants.

Results: The Manhattan plot of gene-based p-values identified the ZNF552 gene as the most significant candidate gene associated with the TSF. A missense variant, rs2288538 (with the major allele encoding tryptophan and the minor allele encoding cysteine), demonstrated strong associations with the TSF (p < 0.0001) and its components, including exhaustion (p = 0.048), low physical activity (p = 0.049), and weak grip strength (p = 0.004). Further verification of the ZNF552 missense variant in follow-up analyses revealed a significant increase in the TSF for CG genotype carriers between age 60 in Wave 1 (0.84 ± 0.9) and age 66 in Wave 2 (1.26 ± 1.26, p = 0.044). These results suggest that rs2288538 may be involved in the physical frailty process. We also examined the correlation between the TSF and cognitive function, as rated by the MMSE, as well as the biological neuroinjury indicator, NfL.

Discussion & Conclusions: The ZNF552 rs2288538 missense variant appears to contribute 5.4% to the total score of frailty (TSF) in carriers of the minor allele. Although this contribution is modest, it reflects an important biological mechanism, as the protein encoded by this gene is highly expressed in the brain's choroid plexus, which is responsible for producing cerebrospinal fluid. These findings provide valuable insights into the understanding of physical frailty in the aging process.