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 journalArticlepeer-review


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 languageEnglish
Pages (from-to)431-439
Number of pages9
JournalJournal of Affective Disorders
Early online date15 May 2023
Publication statusPublished - 15 Aug 2023

Bibliographical note

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 (
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
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.:


  • Depression
  • Glycoprotein acetyls
  • Inflammation
  • Mendelian randomization

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health


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