Insulin resistance: genetic associations with depression and cognition in population based cohorts

Frangou, S. et al. (2019) Insulin resistance: genetic associations with depression and cognition in population based cohorts. Experimental Neurology, 316, pp. 20-26. (doi: 10.1016/j.expneurol.2019.04.001) (PMID:30965038)

Abstract

Insulin resistance, broadly defined as the reduced ability of insulin to exert its biological action, has been associated with depression and cognitive dysfunction in observational studies. However, it is unclear whether these associations are causal and whether they might be underpinned by other shared factors. To address this knowledge gap, we capitalized on the stability of genetic biomarkers through the lifetime, and on their unidirectional relationship with depression and cognition. Specifically, we determined the association between quantitative measures of cognitive function and depression and genetic instruments of insulin resistance traits in two large-scale population samples, the Generation Scotland: Scottish Family Health Study (GS: SFHS; N = 19,994) and in the UK Biobank (N = 331,374). In the GS:SFHS, the polygenic risk score (PRS) for fasting insulin was associated with verbal intelligence and depression while the PRS for the homeostasis model assessment of insulin resistance was associated with verbal intelligence. Despite this overlap in genetic architecture, Mendelian randomization analyses in the GS:SFHS and in the UK Biobank samples did not yield evidence for causal associations from insulin resistance traits to either depression or cognition. These findings may be due to weak genetic instruments, limited cognitive measures and insufficient power but they may also indicate the need to identify other biological mechanisms that may mediate the relationship from insulin resistance to depression and cognition.

• Item Type: Articles
• Additional Information: The research reported here, andthe genotyping of GS:SFHS samples was funded by the Wellcome Trust,(Wellcome Trust Strategic Award‘STratifying Resilience andDepression Longitudinally’(STRADL) Reference 104036/Z/14/Z) andby the Medical Research Council. SF acknowledges support from theNational Institute of Mental Health, USA (R01MH113619;R01MH116147) and the consortium for Psychopathology and Allostaticload across the Life Span (PALS;https://www.pals-network.org) AMMacknowledges thefinancial support received from the Dr. Mortimer andTheresa Sackler Foundation. IJD and AMM are members of TheUniversity of Edinburgh Centre for Cognitive Ageing and CognitiveEpidemiology, part of the cross council Lifelong Health and WellbeingInitiative (MR/K026992/1). Generation Scotland received core supportfrom the Chief Scientist Office of the Scottish Government HealthDirectorates (CZD/16/6) and the Scottish Funding Council (HR03006).Funding from the Biotechnology and Biological Sciences ResearchCouncil and Medical Research Council is gratefully acknowledged.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Padmanabhan, Professor Sandosh
• Authors: Frangou, S., Shirali, M., Adams, M. J., Howard, D. M., Gibson, J., Hall, L. S., Smith, B. H., Padmanabhan, S., Murray, A. D., Porteous, D. J., Haley, C. S., Deary, I. J., Clarke, T.-K., and McIntosh, A. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Experimental Neurology
• Publisher: Elsevier
• ISSN: 0014-4886
• ISSN (Online): 1090-2430
• Published Online: 06 April 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Experimental Neurology 316:20-26
• Publisher Policy: Reproduced under a Creative Commons license