Genetics and biomarkers of frailty : towards individualized management of the frailty syndrome
Author: Mak, Ka Long Jonathan
Date: 2023-11-16
Location: Lecture Hall Petrén, Nobels väg 12B, Karolinska Institutet, Solna
Time: 12.00
Department: Inst för medicinsk epidemiologi och biostatistik / Dept of Medical Epidemiology and Biostatistics
View/ Open:
Thesis (8.175Mb)
Abstract
Frailty is an age-related, dynamic state of multisystem physiological decline and is a
strong predictor of disability and mortality. To move towards an individualized management
of frailty, a better understanding of its biological underpinnings and an early
identification of frail older adults are necessary. The overarching aim of this thesis was to
unravel the genetic, epigenetic, and metabolic determinants of frailty and to develop an
automated frailty assessment tool for the Swedish health system.
In Study I, we calculated a frailty index (FI) for 42,994 Swedish twins and assessed sex differences in the genetic and environmental contributions to the FI. Overall, we observed a higher heritability of the FI in women (52%) than in men (45%). Moreover, the correlations between FI and its two main risk factors, body mass index and education, were mainly attributable to genetic factors and environmental factors shared within twin pairs, respectively, suggesting that different mechanisms may underlie these associations.
In Study II, we examined genetic and environmental influences on the FI trajectories in 2,496 twins followed up to 27 years. A bilinear latent growth curve model best fit the data, indicating a four-to-five times faster FI increase after age 75. While genetic influences were relatively stable across age, individual-specific environmental influences increased substantially after age 75 especially in men, amplifying the overall FI variance in late life.
In Study III, we performed an epigenome-wide analysis in 526 Swedish twins and identified 171 CpG sites associated with the FI at a false discovery rate of <0.05. Many of the identified sites have previously been associated with chronological age and age-related diseases. We further validated five of these sites in an independent sample of 304 Danish twins, which are mapped to genes that may involve in cancer and neurological pathways.
In Study IV, we explored the associations of 168 metabolomic and 32 clinical biomarkers with two measures of frailty using observational and Mendelian randomization analyses. In three population-based studies comprising >100,000 individuals, we identified 34 biomarkers independently and robustly associated with the FI. Specifically, we highlighted a putative causal effect of glycoprotein acetyls, an inflammatory biomarker, on frailty.
In Study V, we developed an electronic frailty index (eFI) using electronic health records from 18,225 patients admitted to nine geriatric clinics in Stockholm. Among the assessed frailty and comorbidity measures, the eFI had the best discriminative ability for mortality.
In summary, this thesis provides novel insights into the biological mechanisms of frailty, suggesting that both genetic and environmental factors play important roles in frailty development, with chronic inflammation as the key underlying mechanism. Moreover, our developed Swedish eFI is a promising tool that can potentially be incorporated in the Swedish health system to guide clinical decisions.
In Study I, we calculated a frailty index (FI) for 42,994 Swedish twins and assessed sex differences in the genetic and environmental contributions to the FI. Overall, we observed a higher heritability of the FI in women (52%) than in men (45%). Moreover, the correlations between FI and its two main risk factors, body mass index and education, were mainly attributable to genetic factors and environmental factors shared within twin pairs, respectively, suggesting that different mechanisms may underlie these associations.
In Study II, we examined genetic and environmental influences on the FI trajectories in 2,496 twins followed up to 27 years. A bilinear latent growth curve model best fit the data, indicating a four-to-five times faster FI increase after age 75. While genetic influences were relatively stable across age, individual-specific environmental influences increased substantially after age 75 especially in men, amplifying the overall FI variance in late life.
In Study III, we performed an epigenome-wide analysis in 526 Swedish twins and identified 171 CpG sites associated with the FI at a false discovery rate of <0.05. Many of the identified sites have previously been associated with chronological age and age-related diseases. We further validated five of these sites in an independent sample of 304 Danish twins, which are mapped to genes that may involve in cancer and neurological pathways.
In Study IV, we explored the associations of 168 metabolomic and 32 clinical biomarkers with two measures of frailty using observational and Mendelian randomization analyses. In three population-based studies comprising >100,000 individuals, we identified 34 biomarkers independently and robustly associated with the FI. Specifically, we highlighted a putative causal effect of glycoprotein acetyls, an inflammatory biomarker, on frailty.
In Study V, we developed an electronic frailty index (eFI) using electronic health records from 18,225 patients admitted to nine geriatric clinics in Stockholm. Among the assessed frailty and comorbidity measures, the eFI had the best discriminative ability for mortality.
In summary, this thesis provides novel insights into the biological mechanisms of frailty, suggesting that both genetic and environmental factors play important roles in frailty development, with chronic inflammation as the key underlying mechanism. Moreover, our developed Swedish eFI is a promising tool that can potentially be incorporated in the Swedish health system to guide clinical decisions.
List of papers:
I. Mak JKL, Reynolds CA, Hägg S, Li X, Ericsson M, Pedersen NL, Jylhävä J, Kuja-Halkola R. Sex differences in genetic and environmental influences on frailty and its relation to body mass index and education. Aging (Albany NY). 2021;13(13):16990–17023.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Mak JKL, Kuja-Halkola R, Bai G, Hassing LB, Pedersen NL, Hägg S, Jylhävä J, Reynolds CA. Genetic and environmental influences on longitudinal frailty trajectories from adulthood into old age. The Journals of Gerontology: Series A. 2023;78(2):333–341.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Mak JKL, Skovgaard AC, Nygaard M, Kananen L, Reynolds CA, Wang Y, Kuja- Halkola R, Karlsson IK, Pedersen NL, Hägg S, Soerensen M, Jylhävä J. Epigenome-wide analysis of frailty: results from two European twin cohorts. [Submitted]
IV. Mak JKL, Kananen L, Qin C, Kuja-Halkola R, Tang B, Lin J, Wang Y, Jääskeläinen T, Koskinen S, Lu Y, Magnusson PKE, Hägg S, Jylhävä J. Unraveling the metabolic underpinnings of frailty using multicohort observational and Mendelian randomization analyses. Aging Cell. 2023;22(8):e13868.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Mak JKL, Hägg S, Eriksdotter M, Annetorp M, Kuja-Halkola R, Kananen L, Boström AM, Kivipelto M, Metzner C, Bäck Jerlardtz V, Engström M, Johnson P, Lundberg LG, Åkesson E, Sühl Öberg C, Olsson M, Cederholm T, Jylhävä J, Religa D. Development of an electronic frailty index for hospitalized older adults in Sweden. The Journals of Gerontology: Series A. 2022;77(11):2311– 2319.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Mak JKL, Reynolds CA, Hägg S, Li X, Ericsson M, Pedersen NL, Jylhävä J, Kuja-Halkola R. Sex differences in genetic and environmental influences on frailty and its relation to body mass index and education. Aging (Albany NY). 2021;13(13):16990–17023.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Mak JKL, Kuja-Halkola R, Bai G, Hassing LB, Pedersen NL, Hägg S, Jylhävä J, Reynolds CA. Genetic and environmental influences on longitudinal frailty trajectories from adulthood into old age. The Journals of Gerontology: Series A. 2023;78(2):333–341.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Mak JKL, Skovgaard AC, Nygaard M, Kananen L, Reynolds CA, Wang Y, Kuja- Halkola R, Karlsson IK, Pedersen NL, Hägg S, Soerensen M, Jylhävä J. Epigenome-wide analysis of frailty: results from two European twin cohorts. [Submitted]
IV. Mak JKL, Kananen L, Qin C, Kuja-Halkola R, Tang B, Lin J, Wang Y, Jääskeläinen T, Koskinen S, Lu Y, Magnusson PKE, Hägg S, Jylhävä J. Unraveling the metabolic underpinnings of frailty using multicohort observational and Mendelian randomization analyses. Aging Cell. 2023;22(8):e13868.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Mak JKL, Hägg S, Eriksdotter M, Annetorp M, Kuja-Halkola R, Kananen L, Boström AM, Kivipelto M, Metzner C, Bäck Jerlardtz V, Engström M, Johnson P, Lundberg LG, Åkesson E, Sühl Öberg C, Olsson M, Cederholm T, Jylhävä J, Religa D. Development of an electronic frailty index for hospitalized older adults in Sweden. The Journals of Gerontology: Series A. 2022;77(11):2311– 2319.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Jylhävä, Juulia
Co-supervisor: Hägg, Sara; Kuja-Halkola, Ralf; Reynolds, Chandra
Issue date: 2023-10-09
Rights:
Publication year: 2023
ISBN: 978-91-8017-107-6
Statistics
Total Visits
Views | |
---|---|
Genetics ... | 926 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Genetics ... | 272 | 349 | 55 | 79 | 64 | 65 | 42 |
File Visits
Views | |
---|---|
Thesis_Jonathan_Mak.pdf | 295 |
Top country views
Views | |
---|---|
Sweden | 341 |
United States | 158 |
Ireland | 100 |
United Kingdom | 69 |
Hong Kong | 52 |
Finland | 25 |
France | 22 |
China | 14 |
Germany | 14 |
South Korea | 13 |
Top cities views
Views | |
---|---|
Skövde | 161 |
Dublin | 64 |
Stockholm | 61 |
Central | 47 |
Toulouse | 18 |
Boydton | 17 |
London | 9 |
Helsinki | 8 |
Kangasala | 8 |
Bromma | 6 |