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

Sophia Frangou (Corresponding Author), Masoud Shirali, Mark J Adams, David M Howard, Jude Gibson, Lynsey S Hall, Blair H Smith, Sandosh Padmanabhan, Alison D Murray, David J Porteous, Chris S Haley, Ian J Deary, Toni-Kim Clarke, Andrew M McIntosh

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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.

Original languageEnglish
Pages (from-to)20-26
Number of pages7
JournalExperimental Neurology
Early online date6 Apr 2019
Publication statusPublished - Jun 2019

Bibliographical note

We are grateful to the families who took part in GS:SFHS, general practitioners and the Scottish School of Primary Care for their help in recruitment, and the whole GS:SFHS team that includes academic researchers, clinic staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. The research reported here, and the genotyping of GS:SFHS samples was funded by the Wellcome Trust, (Wellcome Trust Strategic Award ‘STratifying Resilience and Depression Longitudinally’ (STRADL) Reference 104036/Z/14/Z) and by the Medical Research Council. SF acknowledges support from the National Institute of Mental Health, USA (R01MH113619; R01MH116147) and the consortium for Psychopathology and Allostatic load across the Life Span (PALS; AMM acknowledges the financial support received from the Dr. Mortimer and Theresa Sackler Foundation. IJD and AMM are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged.


  • Insulin resistance
  • Mendelian randomization
  • Polygenic risk scores
  • Genetic association
  • Depression
  • Cognition


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