Associations between IL-6 and trajectories of depressive symptoms across the life course: Evidence from ALSPAC and UK Biobank cohorts

Peripheral inflammatory markers, including serum IL-6, are associated with depression, but less is known about how these markers associate with depression at different stages of the life-course. We examined associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10-28y;N=4,835) and UK Biobank (39-86y;N=39,613) using multi-level growth curve modelling. Models were adjusted for sex, BMI and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire (SMFQ) in ALSPAC (max timepoints=11) and the Patient Health Questionnaire-2 (PHQ-2) in UK Biobank (max timepoints=8). Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 (ALSPAC, age 16y)). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was funded by the Wellcome Trust (Grant No. 108890/Z/15/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. The UK Medical Research Council and Wellcome (Grant No.: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Amelia Edmondson-Stait and Alex Kwong will serve as guarantors 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 the MRC (MR/M006727/1 and GO701503/85179), Wellcome Trust (08426812/Z/07/Z)], Wellcome Trust and MRC (092731), NIH (PD301198-SC101645). UK Biobank Data acquisition and analyses were conducted using the UK Biobank Resource under approved project #4844. ED was supported by the UK Research and Innovation (Grant No. EP/S02431X/1), UK Research and Innovation Centre for Doctoral Training in Biomedical AI at the University of Edinburgh, School of Informatics. ASFK is funded by a Wellcome Early Career Award (Grant ref: 227063/Z/23/Z). AMM is supported by Wellcome Trust Investigator Award (Grant ref: 220857/Z/20/Z). GMK acknowledges funding support from the UK Medical Research Council (MRC) via the Integrative Epidemiology Unit (IEU) at the University of Bristol (MC\_UU\_00032/06), and additional funding from the Wellcome Trust (201486/Z/16/Z and 201486/B/16/Z), the MRC (MR/W014416/1; MR/S037675/1; and The CHECKPOINT Hub, APP4735-GTEE-2024), and the UK National Institute of Health and Care Research (NIHR) Bristol Biomedical Research Centre (NIHR 203315). The views expressed are those of the authors and not necessarily those of the UK NIHR or the Department of Health and Social Care. We are extremely grateful to all the families who took part in both the ALSPAC and UK Biobank studies, the whole ALSPAC and UK Biobank teams, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, midwifes and nurses. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for UK Biobank analyses was granted by the North West Multi-centre Research Ethics Committee as a Research Tissue Bank approval (reference: 11/NW/0382). Ethical approval for Avon Longitudinal Study of Parents And Children was obtained from the Avon Longitudinal Study of Parents And Children Ethics and Law Committee and the Local Research Ethics Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in the present study is available from UK Biobank and ALSPAC with restrictions applied. Data were used under license and thus not publicly available. Access to the UK Biobank data can be requested through a standard protocol (https://www.ukbiobank.ac.uk/register-apply/). The ALSPAC study website contains details of all data available: http://www.bristol.ac.uk/alspac/researchers/our-data.