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

Sophia Frangou; 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

doi:10.1016/j.expneurol.2019.04.001

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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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 language	English
Pages (from-to)	20-26
Number of pages	7
Journal	Experimental Neurology
Volume	316
Early online date	6 Apr 2019
DOIs	https://doi.org/10.1016/j.expneurol.2019.04.001
Publication status	Published - 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; https://www.pals-network.org) 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.

Keywords

Insulin resistance
Mendelian randomization
Polygenic risk scores
Genetic association
Depression
Cognition

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10.1016/j.expneurol.2019.04.001Licence: CC BY-NC-ND

Insulin resistance Genetic associations with depression and cognition in population based cohorts
© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)
Final published version, 397 KBLicence: CC BY-NC-ND

Cite this

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

Frangou, S, Shirali, M, Adams, MJ, Howard, DM, Gibson, J, Hall, LS, Smith, BH, Padmanabhan, S, Murray, AD, Porteous, DJ, Haley, CS, Deary, IJ, Clarke, T-K & McIntosh, AM 2019, 'Insulin resistance: Genetic associations with depression and cognition in population based cohorts', Experimental Neurology, vol. 316, pp. 20-26. https://doi.org/10.1016/j.expneurol.2019.04.001

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title = "Insulin resistance: Genetic associations with depression and cognition in population based cohorts",

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.",

keywords = "Insulin resistance, Mendelian randomization, Polygenic risk scores, Genetic association, Depression, Cognition",

author = "Sophia Frangou and Masoud Shirali and Adams, {Mark J} and Howard, {David M} and Jude Gibson and Hall, {Lynsey S} and Smith, {Blair H} and Sandosh Padmanabhan and Murray, {Alison D} and Porteous, {David J} and Haley, {Chris S} and Deary, {Ian J} and Toni-Kim Clarke and McIntosh, {Andrew M}",

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 {\textquoteleft}STratifying Resilience and Depression Longitudinally{\textquoteright} (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; https://www.pals-network.org) 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.",

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doi = "10.1016/j.expneurol.2019.04.001",

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AU - Frangou, Sophia

AU - Shirali, Masoud

AU - Adams, Mark J

AU - Howard, David M

AU - Gibson, Jude

AU - Hall, Lynsey S

AU - Smith, Blair H

AU - Padmanabhan, Sandosh

AU - Murray, Alison D

AU - Porteous, David J

AU - Haley, Chris S

AU - Deary, Ian J

AU - Clarke, Toni-Kim

AU - McIntosh, Andrew M

N1 - 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; https://www.pals-network.org) 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.

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N2 - 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.

AB - 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.

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KW - Depression

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

Abstract

Bibliographical note

Keywords

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