Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses

Daisy C.P. Crick; Eleanor Sanderson; Hannah Jones; Neil Goulding; Maria Carolina Borges; Gemma Clayton; Alice R. Carter; Sarah Halligan; Deborah A. Lawlor; Golam M. Khandaker; Abigail Fraser

doi:10.1016/j.jad.2023.05.033

Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses

Daisy C.P. Crick, Eleanor Sanderson, Hannah Jones, Neil Goulding, Maria Carolina Borges, Gemma Clayton, Alice R. Carter, Sarah Halligan, Deborah A. Lawlor, Golam M. Khandaker, Abigail Fraser

Research output: Contribution to journal › Article › peer-review

2 Citations (SciVal)

Abstract

Background: Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression. Methods: Using data from the ALSPAC birth cohort (n = 4021; 42.18 % male), we used multivariable regression to investigate bidirectional longitudinal associations of GlycA and depression and depression symptoms, assessed at ages 18y and 24y. We used two-sample Mendelian randomization (MR) to investigate potential causality and directionality. Genetic variants for GlycA were obtained from UK Biobank (UKB) (N = 115,078); for depression from the Psychiatric Genomics Consortium and UKB (N = 500,199); and for depressive symptoms (N = 161,460) from the Social Science Genetic Association Consortium. In addition to the Inverse Variance Weighted method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR adjusting for body mass index (BMI) due to known genetic correlation between inflammation, depression and BMI. Results: In the cohort analysis, after adjusting for potential confounders we found no evidence of associations between GlycA and depression symptoms score or vice versa. We observed an association between GlycA and depression (OR = 1∙18, 95 % CI: 1∙03–1∙36). MR suggested no causal effect of GlycA on depression, but there was a causal effect of depression on GlycA (mean difference in GlycA = 0∙09; 95 % CI: 0∙03–0∙16), which was maintained in some, but not all, sensitivity analyses. Limitations: The GWAS sample overlap could incur bias. Conclusion: We found no consistent evidence for an effect of GlycA on depression. There was evidence that depression increases GlycA in the MR analysis, but this may be confounded/mediated by BMI.

Original language	English
Pages (from-to)	431-439
Number of pages	9
Journal	Journal of Affective Disorders
Volume	335
Early online date	15 May 2023
DOIs	https://doi.org/10.1016/j.jad.2023.05.033
Publication status	Published - 15 Aug 2023

Bibliographical note

Funding
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 DC will serve as
guarantor for the contents of this paper. A comprehensive list of grants
funding is available on the ALSPAC website (http://www.bristol.ac.
uk/alspac/external/documents/grant-acknowledgements.pdf); This
research was specifically funded by Wellcome Trust and MRC (core)
(Grant ref.: 76467/Z/05/Z), MRC (Grant ref.: MR/L022206/1) and
Wellcome Trust (Grant ref.: 8426812/Z/07/Z).
This work was supported in part by the GW4 BIOMED DTP (D.C.,
MR/N0137941/), awarded to the Universities of Bath, Bristol, Cardiff
and Exeter from the Medical Research Council (MRC)/UKRI.
GMK acknowledges funding support from the Wellcome Trust (grant
code: 201486/Z/16/Z), the MQ: Transforming Mental Health (grant
code: MQDS17/40), the Medical Research Council UK (grant code:
MC_PC_17213 and MR/S037675/1) and the BMA Foundation (J Moulton grant 2019).
AF, GK and others works in the MRC Integrative Epidemiology Unit
(MC_UU_00011).
ARC and MCB work in the MRC Integrative Epidemiology Unit
(MC_UU_00011/6) and are supported by the University of Bristol British
Heart Foundation Accelerator Award (AA/18/7/34219).
The research by MCB was supported by a UK Medical Research
Council (MRC) Skills Development Fellowship (MR/P014054/1) and a
Vice-Chancellor's Fellowship from the University of Bristol.
NG was supported by the John Templeton Foundation (Grant ref.:
61917)

Funding

GMK acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z ), the MQ: Transforming Mental Health (grant code: MQDS17/40 ), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1 ) and the BMA Foundation (J Moulton grant 2019 ). ARC and MCB work in the MRC Integrative Epidemiology Unit (MC_UU_00011/6) and are supported by the University of Bristol British Heart Foundation Accelerator Award ( AA/18/7/34219 ). This work was supported in part by the GW4 BIOMED DTP (D.C., MR/N0137941/ ), awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. This work was carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/. 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. 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 DC will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by Wellcome Trust and MRC (core) (Grant ref.: 76467/Z/05/Z), MRC (Grant ref.: MR/L022206/1) and Wellcome Trust (Grant ref.: 8426812/Z/07/Z). This work was supported in part by the GW4 BIOMED DTP (D.C. MR/N0137941/), awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. GMK acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the MQ: Transforming Mental Health (grant code: MQDS17/40), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1) and the BMA Foundation (J Moulton grant 2019). AF, GK and others works in the MRC Integrative Epidemiology Unit (MC_UU_00011). ARC and MCB work in the MRC Integrative Epidemiology Unit (MC_UU_00011/6) and are supported by the University of Bristol British Heart Foundation Accelerator Award (AA/18/7/34219). The research by MCB was supported by a UK Medical Research Council (MRC) Skills Development Fellowship (MR/P014054/1) and a Vice-Chancellor's Fellowship from the University of Bristol. NG was supported by the John Templeton Foundation (Grant ref.: 61917). NG was supported by the John Templeton Foundation (Grant ref.: 61917 ). 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 DC will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ); This research was specifically funded by Wellcome Trust and MRC (core) (Grant ref.: 76467/Z/05/Z ), MRC (Grant ref.: MR/L022206/1 ) and Wellcome Trust (Grant ref.: 8426812/Z/07/Z ). The research by MCB was supported by a UK Medical Research Council (MRC) Skills Development Fellowship ( MR/P014054/1 ) and a Vice-Chancellor's Fellowship from the University of Bristol .

Keywords

ALSPAC
Depression
Glycoprotein acetyls
Inflammation
Mendelian randomization

ASJC Scopus subject areas

Clinical Psychology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jad.2023.05.033Licence: CC BY

Cite this

Crick, D. C. P., Sanderson, E., Jones, H., Goulding, N., Borges, M. C., Clayton, G., Carter, A. R., Halligan, S., Lawlor, D. A., Khandaker, G. M., & Fraser, A. (2023). Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses. Journal of Affective Disorders, 335, 431-439. https://doi.org/10.1016/j.jad.2023.05.033

Crick, DCP, Sanderson, E, Jones, H, Goulding, N, Borges, MC, Clayton, G, Carter, AR, Halligan, S, Lawlor, DA, Khandaker, GM & Fraser, A 2023, 'Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses', Journal of Affective Disorders, vol. 335, pp. 431-439. https://doi.org/10.1016/j.jad.2023.05.033

@article{b777caa3afca4a419edeccab1c4e1ddb,

title = "Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses",

abstract = "Background: Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression. Methods: Using data from the ALSPAC birth cohort (n = 4021; 42.18 % male), we used multivariable regression to investigate bidirectional longitudinal associations of GlycA and depression and depression symptoms, assessed at ages 18y and 24y. We used two-sample Mendelian randomization (MR) to investigate potential causality and directionality. Genetic variants for GlycA were obtained from UK Biobank (UKB) (N = 115,078); for depression from the Psychiatric Genomics Consortium and UKB (N = 500,199); and for depressive symptoms (N = 161,460) from the Social Science Genetic Association Consortium. In addition to the Inverse Variance Weighted method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR adjusting for body mass index (BMI) due to known genetic correlation between inflammation, depression and BMI. Results: In the cohort analysis, after adjusting for potential confounders we found no evidence of associations between GlycA and depression symptoms score or vice versa. We observed an association between GlycA and depression (OR = 1∙18, 95 % CI: 1∙03–1∙36). MR suggested no causal effect of GlycA on depression, but there was a causal effect of depression on GlycA (mean difference in GlycA = 0∙09; 95 % CI: 0∙03–0∙16), which was maintained in some, but not all, sensitivity analyses. Limitations: The GWAS sample overlap could incur bias. Conclusion: We found no consistent evidence for an effect of GlycA on depression. There was evidence that depression increases GlycA in the MR analysis, but this may be confounded/mediated by BMI.",

keywords = "ALSPAC, Depression, Glycoprotein acetyls, Inflammation, Mendelian randomization",

author = "Crick, {Daisy C.P.} and Eleanor Sanderson and Hannah Jones and Neil Goulding and Borges, {Maria Carolina} and Gemma Clayton and Carter, {Alice R.} and Sarah Halligan and Lawlor, {Deborah A.} and Khandaker, {Golam M.} and Abigail Fraser",

note = "Funding 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 DC will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac. uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by Wellcome Trust and MRC (core) (Grant ref.: 76467/Z/05/Z), MRC (Grant ref.: MR/L022206/1) and Wellcome Trust (Grant ref.: 8426812/Z/07/Z). This work was supported in part by the GW4 BIOMED DTP (D.C., MR/N0137941/), awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. GMK acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the MQ: Transforming Mental Health (grant code: MQDS17/40), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1) and the BMA Foundation (J Moulton grant 2019). AF, GK and others works in the MRC Integrative Epidemiology Unit (MC_UU_00011). ARC and MCB work in the MRC Integrative Epidemiology Unit (MC_UU_00011/6) and are supported by the University of Bristol British Heart Foundation Accelerator Award (AA/18/7/34219). The research by MCB was supported by a UK Medical Research Council (MRC) Skills Development Fellowship (MR/P014054/1) and a Vice-Chancellor's Fellowship from the University of Bristol. NG was supported by the John Templeton Foundation (Grant ref.: 61917)",

year = "2023",

month = aug,

day = "15",

doi = "10.1016/j.jad.2023.05.033",

language = "English",

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TY - JOUR

T1 - Glycoprotein acetyls and depression

T2 - Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses

AU - Crick, Daisy C.P.

AU - Sanderson, Eleanor

AU - Jones, Hannah

AU - Goulding, Neil

AU - Borges, Maria Carolina

AU - Clayton, Gemma

AU - Carter, Alice R.

AU - Halligan, Sarah

AU - Lawlor, Deborah A.

AU - Khandaker, Golam M.

AU - Fraser, Abigail

N1 - Funding 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 DC will serve as guarantor for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac. uk/alspac/external/documents/grant-acknowledgements.pdf); This research was specifically funded by Wellcome Trust and MRC (core) (Grant ref.: 76467/Z/05/Z), MRC (Grant ref.: MR/L022206/1) and Wellcome Trust (Grant ref.: 8426812/Z/07/Z). This work was supported in part by the GW4 BIOMED DTP (D.C., MR/N0137941/), awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI. GMK acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the MQ: Transforming Mental Health (grant code: MQDS17/40), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1) and the BMA Foundation (J Moulton grant 2019). AF, GK and others works in the MRC Integrative Epidemiology Unit (MC_UU_00011). ARC and MCB work in the MRC Integrative Epidemiology Unit (MC_UU_00011/6) and are supported by the University of Bristol British Heart Foundation Accelerator Award (AA/18/7/34219). The research by MCB was supported by a UK Medical Research Council (MRC) Skills Development Fellowship (MR/P014054/1) and a Vice-Chancellor's Fellowship from the University of Bristol. NG was supported by the John Templeton Foundation (Grant ref.: 61917)

PY - 2023/8/15

Y1 - 2023/8/15

N2 - Background: Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression. Methods: Using data from the ALSPAC birth cohort (n = 4021; 42.18 % male), we used multivariable regression to investigate bidirectional longitudinal associations of GlycA and depression and depression symptoms, assessed at ages 18y and 24y. We used two-sample Mendelian randomization (MR) to investigate potential causality and directionality. Genetic variants for GlycA were obtained from UK Biobank (UKB) (N = 115,078); for depression from the Psychiatric Genomics Consortium and UKB (N = 500,199); and for depressive symptoms (N = 161,460) from the Social Science Genetic Association Consortium. In addition to the Inverse Variance Weighted method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR adjusting for body mass index (BMI) due to known genetic correlation between inflammation, depression and BMI. Results: In the cohort analysis, after adjusting for potential confounders we found no evidence of associations between GlycA and depression symptoms score or vice versa. We observed an association between GlycA and depression (OR = 1∙18, 95 % CI: 1∙03–1∙36). MR suggested no causal effect of GlycA on depression, but there was a causal effect of depression on GlycA (mean difference in GlycA = 0∙09; 95 % CI: 0∙03–0∙16), which was maintained in some, but not all, sensitivity analyses. Limitations: The GWAS sample overlap could incur bias. Conclusion: We found no consistent evidence for an effect of GlycA on depression. There was evidence that depression increases GlycA in the MR analysis, but this may be confounded/mediated by BMI.

AB - Background: Inflammation is associated with depression, but causality remains unclear. We investigated potential causality and direction of effect between inflammation and depression. Methods: Using data from the ALSPAC birth cohort (n = 4021; 42.18 % male), we used multivariable regression to investigate bidirectional longitudinal associations of GlycA and depression and depression symptoms, assessed at ages 18y and 24y. We used two-sample Mendelian randomization (MR) to investigate potential causality and directionality. Genetic variants for GlycA were obtained from UK Biobank (UKB) (N = 115,078); for depression from the Psychiatric Genomics Consortium and UKB (N = 500,199); and for depressive symptoms (N = 161,460) from the Social Science Genetic Association Consortium. In addition to the Inverse Variance Weighted method, we used sensitivity analyses to strengthen causal inference. We conducted multivariable MR adjusting for body mass index (BMI) due to known genetic correlation between inflammation, depression and BMI. Results: In the cohort analysis, after adjusting for potential confounders we found no evidence of associations between GlycA and depression symptoms score or vice versa. We observed an association between GlycA and depression (OR = 1∙18, 95 % CI: 1∙03–1∙36). MR suggested no causal effect of GlycA on depression, but there was a causal effect of depression on GlycA (mean difference in GlycA = 0∙09; 95 % CI: 0∙03–0∙16), which was maintained in some, but not all, sensitivity analyses. Limitations: The GWAS sample overlap could incur bias. Conclusion: We found no consistent evidence for an effect of GlycA on depression. There was evidence that depression increases GlycA in the MR analysis, but this may be confounded/mediated by BMI.

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KW - Glycoprotein acetyls

KW - Inflammation

KW - Mendelian randomization

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SP - 431

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ER -

Glycoprotein acetyls and depression: Testing for directionality and potential causality using longitudinal data and Mendelian randomization analyses

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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