The brain insulin receptor gene network and associations with frailty index

Author:

Selenius Jannica S12,Silveira Patricia P345,Haapanen Markus J126,von Bonsdorff Mikaela17,Lahti Jari189,Eriksson Johan G12101112,Wasenius Niko S12

Affiliation:

1. Folkhälsan Research Center , Helsinki , Finland

2. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital , Helsinki , Finland

3. Department of Psychiatry , Faculty of Medicine and Health Sciences, , Verdun QCH4H1R3 , Canada

4. McGill University , Faculty of Medicine and Health Sciences, , Verdun QCH4H1R3 , Canada

5. Ludmer Centre for Neuroinformatic and Mental Health, Douglas Mental Health University Institute, McGill University , Verdun QCH4H1R3 , Canada

6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , Stockholm , Sweden

7. Gerontology Research Center and Faculty of Sport and Health Sciences, University of Jyväskylä , Jyväskylä , Finland

8. Department of Psychology and Logopedics, University of Helsinki , Haartmaninkatu 8, 00014 Helsinki , Finland

9. Turku Institute for Advanced Studies, University of Turku , 20014 Turku , Finland

10. Department of Obstetrics & Gynecology and Human Potential Translational Research Program , Yong Loo Lin School of Medicine, , Singapore

11. National University of Singapore , Yong Loo Lin School of Medicine, , Singapore

12. Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology and Research (A*STAR) , Singapore

Abstract

Abstract Objective To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up. Methods This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001–2004, 2011–2013 and 2017–2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age. Results The FI levels of women were 1.19%-points (95% CI 0.12–2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43). Conclusions Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.

Funder

Finnish Foundation for Cardiovascular Research

Finnish Foundation for Diabetes Research

Juho Vainio Foundation

Academy of Finland

Novo Nordisk Foundation

Signe and Ane Gyllenberg Foundation

Samfundet Folkhälsan

Finska Läkaresällskapet

Liv och Hälsa

European Commission FP7

DynaHealth

EU Horizon 2020

Canadian Institutes of Health Research

Publisher

Oxford University Press (OUP)

Reference59 articles.

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