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

Sophia Frangou (Lead / 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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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.

Original languageEnglish
Pages (from-to)20-26
Number of pages7
JournalExperimental Neurology
Volume316
Early online date6 Apr 2019
DOIs
Publication statusPublished - Jun 2019

Keywords

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

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    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., & McIntosh, A. M. (2019). Insulin resistance: Genetic associations with depression and cognition in population based cohorts. Experimental Neurology, 316, 20-26. https://doi.org/10.1016/j.expneurol.2019.04.001