The Influence of Phenotyping Method on Structural Neuroimaging Associations with Depression in UK Biobank

Background Depression is assessed in many different ways, with large population studies often relying on minimal phenotyping approaches. Genetic results suggest that more formal clinical diagnoses and simpler self-report measures of depression show some core similarities, but also important differences. It is not yet clear whether this is also the case for neuroimaging measures. Methods We studied 39,300 UK Biobank imaging participants (20,701 female; aged 44.6 to 82.3 years, M = 64.1, SD = 7.5) with structural neuroimaging (T1 and DTI) and depression data. Depression phenotypes included a minmal single-item self-report measure, an intermediate symptom-based measure of ‘probable’ depression, and a more clinically robust measure based on DSM-IV criteria. We tested i) associations between brain structural measures and each depression phenotype, and ii) the effects of depression phenotype on these associations. Results Small depression-brain structure associations (β < 0.1) were significant after FDR correction for many global and regional metrics for all three phenotypes. The most consistent imaging associations across depression phenotypes were for measures of white matter integrity. There were small but significant effects of phenotype definition primarily for cortical thickness, which showed stronger negative associations with Self-reported Depression than the symptom-based measures. Conclusion Similar to previous genetic studies, we found some consistent associations indicating a core component of depression across phenotypes, and some additional associations that were phenotype-specific. Although these specific results did not relate to depth of phenotyping as expected, effects of phenotype definition are still an important consideration for future depression research. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funded by Wellcome Trust grant 104036 project Stratifying Resilience and Depression Longitudinally (STRADL) ### 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: Used data from UK Biobank (application ID 4844) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data are available to others from UK Biobank