Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses

Chloe Slaney; Hannah M Sallis; Hannah J Jones; Christina Dardani; Charge Inflammation Working Group; Kate Tilling; Marcus R Munafò; George Davey Smith; Liam Mahedy; Golam M Khandaker

doi:10.1016/j.bbi.2023.02.010

Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses

Chloe Slaney^*, Hannah M Sallis, Hannah J Jones, Christina Dardani, Charge Inflammation Working Group, Kate Tilling, Marcus R Munafò, George Davey Smith, Liam Mahedy, Golam M Khandaker

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

8 Citations (Scopus)

Abstract

Background

Inflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear.

Methods

In a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability.

Results

In the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, −0.02 [95 % confidence interval (CI) −0.06 to 0.02, p = 0.27] to 0.02 [95 % CI −0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, −0.73 [95 % CI −2.47 to 1.01, p = 0.41] to 0.21 [95 % CI −1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, −0.02 [95 % CI −0.05 to 0.01, p = 0.12] to 0.03 [95 % CI −0.01 to 0.07, p = 0.19]).

Conclusions

Our MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.

Original language	English
Pages (from-to)	30-42
Number of pages	13
Journal	Brain, Behavior, and Immunity
Volume	110
Early online date	13 Feb 2023
DOIs	https://doi.org/10.1016/j.bbi.2023.02.010 https://doi.org/10.1016/j.bbi.2023.02.010
Publication status	Published - 1 May 2023

Bibliographical note

Funding Information:
This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Members of the CHARGE Inflammation Working Group are Emelia Benjamin, Daniel I. Chasman, Abbas Dehghan, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Behrooz Z. Alizadeh, Symen Ligthart, Josh Bis, Gudny Eiriksdottir, Nathan Pankratz, Myron Gross, Alex Rainer, Harold Snieder, James G. Wilson, Bruce M. Psaty, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Lude Franke, Terho Lehtimaki, Wolfgang Koenig, Yalda Jamshidi, Sophie Siest, Ali Abbasi, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Ilja M. Nolte, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey Smith, Alanna C. Morrison, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, Eric Boerwinkle, J. Rotter, Ken Rice, Leslie Lange, Markus Perola, Eco de Geus, Andrew P. Morris, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, and Eline P. Slagboom. Ethics statement, Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee (http://www.bristol.ac.uk/alspac/researchers/research-ethics/) and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. ALSPAC study data were collected and managed using REDCap electronic data capture tools hosted at the University of Bristol (Harris et al. 2009). REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies.

Funding Information:
This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1).

Funding Information:
This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Funding Information:
The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe.

Publisher Copyright:
© 2023 The Authors

Structured keywords

ALSPAC
Bristol Population Health Science Institute

Access to Document

10.1016/j.bbi.2023.02.010
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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23
Project: Research

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities
Sadaf R Alam (Manager), Steven A Chapman (Manager), Polly E Eccleston (Other), Simon H Atack (Other) & D A G Williams (Manager)
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Cite this

Slaney, C., Sallis, H. M., Jones, H. J., Dardani, C., Inflammation Working Group, C., Tilling, K., Munafò, M. R., Davey Smith, G., Mahedy, L., & Khandaker, G. M. (2023). Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses. Brain, Behavior, and Immunity, 110, 30-42. https://doi.org/10.1016/j.bbi.2023.02.010, https://doi.org/10.1016/j.bbi.2023.02.010

@article{057d701ceb7f4faa8321f4b3d6e80303,

title = "Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses",

abstract = "BackgroundInflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear.MethodsIn a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability.ResultsIn the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, −0.02 [95 % confidence interval (CI) −0.06 to 0.02, p = 0.27] to 0.02 [95 % CI −0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, −0.73 [95 % CI −2.47 to 1.01, p = 0.41] to 0.21 [95 % CI −1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, −0.02 [95 % CI −0.05 to 0.01, p = 0.12] to 0.03 [95 % CI −0.01 to 0.07, p = 0.19]).ConclusionsOur MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.",

author = "Chloe Slaney and Sallis, {Hannah M} and Jones, {Hannah J} and Christina Dardani and {Inflammation Working Group}, Charge and Kate Tilling and Munaf{\`o}, {Marcus R} and {Davey Smith}, George and Liam Mahedy and Khandaker, {Golam M}",

note = "Funding Information: This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Members of the CHARGE Inflammation Working Group are Emelia Benjamin, Daniel I. Chasman, Abbas Dehghan, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Behrooz Z. Alizadeh, Symen Ligthart, Josh Bis, Gudny Eiriksdottir, Nathan Pankratz, Myron Gross, Alex Rainer, Harold Snieder, James G. Wilson, Bruce M. Psaty, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Lude Franke, Terho Lehtimaki, Wolfgang Koenig, Yalda Jamshidi, Sophie Siest, Ali Abbasi, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Ilja M. Nolte, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey Smith, Alanna C. Morrison, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, Eric Boerwinkle, J. Rotter, Ken Rice, Leslie Lange, Markus Perola, Eco de Geus, Andrew P. Morris, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, and Eline P. Slagboom. Ethics statement, Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee (http://www.bristol.ac.uk/alspac/researchers/research-ethics/) and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. ALSPAC study data were collected and managed using REDCap electronic data capture tools hosted at the University of Bristol (Harris et al. 2009). REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies. Funding Information: This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1). Funding Information: This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = may,

day = "1",

doi = "10.1016/j.bbi.2023.02.010",

language = "English",

volume = "110",

pages = "30--42",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

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Slaney, C , Sallis, HM , Jones, HJ , Dardani, C, Inflammation Working Group, C, Tilling, K , Munafò, MR , Davey Smith, G, Mahedy, L & Khandaker, GM 2023, 'Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses', Brain, Behavior, and Immunity, vol. 110, pp. 30-42. https://doi.org/10.1016/j.bbi.2023.02.010, https://doi.org/10.1016/j.bbi.2023.02.010

TY - JOUR

T1 - Association between inflammation and cognition

T2 - triangulation of evidence using a population-based cohort and Mendelian randomization analyses

AU - Slaney, Chloe

AU - Sallis, Hannah M

AU - Jones, Hannah J

AU - Dardani, Christina

AU - Inflammation Working Group, Charge

AU - Tilling, Kate

AU - Munafò, Marcus R

AU - Davey Smith, George

AU - Mahedy, Liam

AU - Khandaker, Golam M

N1 - Funding Information: This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. Members of the CHARGE Inflammation Working Group are Emelia Benjamin, Daniel I. Chasman, Abbas Dehghan, Tarunveer Singh Ahluwalia, James Meigs, Russell Tracy, Behrooz Z. Alizadeh, Symen Ligthart, Josh Bis, Gudny Eiriksdottir, Nathan Pankratz, Myron Gross, Alex Rainer, Harold Snieder, James G. Wilson, Bruce M. Psaty, Josee Dupuis, Bram Prins, Urmo Vaso, Maria Stathopoulou, Lude Franke, Terho Lehtimaki, Wolfgang Koenig, Yalda Jamshidi, Sophie Siest, Ali Abbasi, Andre G. Uitterlinden, Mohammadreza Abdollahi, Renate Schnabel, Ursula M. Schick, Ilja M. Nolte, Aldi Kraja, Yi-Hsiang Hsu, Daniel S. Tylee, Alyson Zwicker, Rudolf Uher, George Davey Smith, Alanna C. Morrison, Andrew Hicks, Cornelia M. van Duijn, Cavin Ward-Caviness, Eric Boerwinkle, J. Rotter, Ken Rice, Leslie Lange, Markus Perola, Eco de Geus, Andrew P. Morris, Kari Matti Makela, David Stacey, Johan Eriksson, Tim M. Frayling, and Eline P. Slagboom. Ethics statement, Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee (http://www.bristol.ac.uk/alspac/researchers/research-ethics/) and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. ALSPAC study data were collected and managed using REDCap electronic data capture tools hosted at the University of Bristol (Harris et al. 2009). REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies. Funding Information: This work was also supported by the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/7). GMK acknowledges funding support from the Wellcome Trust (Grant No. 201486/Z/16/Z), and the UK Medical Research Council (Grant No. MC_PC_17213, Grant No. MR/S037675/1, and Grant No. MR/W014416/1). HJ is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and KT work in the MRC Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/3). CD is supported by an MRC Integrative Epidemiology Unit Fellowship (MC_UU_00011/1). Funding Information: This work is supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 204813/Z/16/Z]. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Funding Information: The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and CS will serve as a guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPC website (grant-acknowledgements.pdf (bristol.ac.uk); this research was specifically funded by Wellcome Trust and MRC (Grant Ref: 076467/Z/05/Z; MR/L022206/1). GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. Publisher Copyright: © 2023 The Authors

PY - 2023/5/1

Y1 - 2023/5/1

N2 - BackgroundInflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear.MethodsIn a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability.ResultsIn the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, −0.02 [95 % confidence interval (CI) −0.06 to 0.02, p = 0.27] to 0.02 [95 % CI −0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, −0.73 [95 % CI −2.47 to 1.01, p = 0.41] to 0.21 [95 % CI −1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, −0.02 [95 % CI −0.05 to 0.01, p = 0.12] to 0.03 [95 % CI −0.01 to 0.07, p = 0.19]).ConclusionsOur MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.

AB - BackgroundInflammation is associated with cognitive functioning and dementia in older adults, but whether inflammation is related to cognitive functioning in youth and whether these associations are causal remains unclear.MethodsIn a population-based cohort (Avon Longitudinal Study of Parents and Children; ALSPAC), we investigated cross-sectional associations of inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6] and Glycoprotein acetyls [GlycA]) with measures of cold (working memory, response inhibition) and hot (emotion recognition) cognition at age 24 (N = 3,305 in multiple imputation models). Furthermore, we conducted one-sample and two-sample bidirectional Mendelian randomization (MR) analyses to examine potential causal effects of genetically-proxied inflammatory markers (CRP, GlycA, IL-6, IL-6 receptor, soluble IL-6 receptor) on cognitive measures (above) and on general cognitive ability.ResultsIn the ALSPAC cohort, there was limited evidence of an association between standardised inflammatory markers and standardised cognitive measures at age 24 after adjusting for potential confounders (N = 3,305; beta range, −0.02 [95 % confidence interval (CI) −0.06 to 0.02, p = 0.27] to 0.02 [95 % CI −0.02 to 0.05, p = 0.33]). Similarly, we found limited evidence of potential effects of 1-unit increase in genetically-proxied inflammatory markers on standardised working memory, emotion recognition or response inhibition in one-sample MR using ALSPAC data (beta range, −0.73 [95 % CI −2.47 to 1.01, p = 0.41] to 0.21 [95 % CI −1.42 to 1.84, p = 0.80]; or on standardised general cognitive ability in two-sample MR using the latest Genome-Wide Association Study (GWAS) datasets (inverse-variance weighted beta range, −0.02 [95 % CI −0.05 to 0.01, p = 0.12] to 0.03 [95 % CI −0.01 to 0.07, p = 0.19]).ConclusionsOur MR findings do not provide strong evidence of a potential causal effect of inflammatory markers (CRP, IL-6, IL-6 receptor, GlycA) on the cognitive functions examined here. Given the large confidence intervals in the one-sample MR, larger GWAS of specific cognitive measures are needed to enable well-powered MR analyses to investigate whether inflammation causally influences specific cognitive domains.

U2 - 10.1016/j.bbi.2023.02.010

DO - 10.1016/j.bbi.2023.02.010

M3 - Article (Academic Journal)

C2 - 36791891

SN - 0889-1591

VL - 110

SP - 30

EP - 42

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

Association between inflammation and cognition: triangulation of evidence using a population-based cohort and Mendelian randomization analyses

Abstract

Bibliographical note

Structured keywords

Access to Document

Handle.net

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Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Equipment

HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

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