Abstract
Determining a diagnosis of major depressive disorder (MDD) is complex, involving consideration and rating of a variety of different components. These include number of symptoms over an agreed threshold, symptom duration, functional impairment, persistence of symptoms within an episode, and symptom recurrence. While these components are generally accepted amongst physicians, it is unknown whether they reflect partly distinct biology between phenotypes. The aim of this study was to investigate how the genetic aetiology varies in the presence of different MDD components.
Thirty-two depression phenotypes which systematically incorporate the MDD components were created using the mental health questionnaire data within the UK Biobank. SNP-based heritabilities and genetic correlations with three previously defined major depression phenotypes were calculated (broad depression, Psychiatric Genomics Consortium (PGC) defined depression and 23andMe, Inc. self-reported depression) and differences between estimates analysed.
All phenotypes were heritable (h2SNP range: 0.102 – 0.162) and showed substantial genetic correlations with other major depression phenotypes (Rg range: 0.651 – 0.894 (PGC); 0.652 – 0.837 (23andMe); 0.699 – 0.900 (broad depression)). The requirement for 5 or more symptoms and for a long episode duration had the strongest effect on SNP-based heritability, in the positive and negative direction respectively (1.4% average increase; 2.7% average decrease). No significant differences were noted between genetic correlations.
While there is some variation, the two cardinal symptoms, depressed mood and anhedonia, largely reflect the genetic aetiology of phenotypes incorporating more MDD components. These components may appropriately index for severity, however, the genetic component between phenotypes incorporating none and all components is comparable.
Competing Interest Statement
Cathryn M Lewis reports having received fees from Myriad Neuroscience. Bradley S Jermy, Kylie P Glanville, Jonathan RI Coleman and Evangelos Vassos reported no biomedical financial interests or potential conflicts of interest.
Funding Statement
CML is funded by the Medical Research Council (N015746/1). This study represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
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:
Ethics approval for the UK Biobank study was obtained from the North West Centre for Research Ethics Committee (11/NW/0382). This study was granted access to UK Biobank data after registration under approved application 18177. The MDD GWAS summary statistics results from 23andMe were available through a Data Transfer Agreement between 23andMe Inc. and Kings College London. Only summary statistics were shared with no individual level data. 23andMe participants provided informed consent and participated in the research online. The 23andMe protocol was approved by an external Association for the Accreditation of Human Research Protection Programs accredited Institutional Review Board, Ethical and Independent Review Services. Participants were included in the analysis on the basis of consent status as checked at the time data analyses were initiated. Access to the Psychiatric Genomics Consortium summary statistics for use in this study was approved following registration to a data download agreement at the following url: https://www.med.unc.edu/pgc/download-results/. The original data of the PGC summary statistics is a meta-analysis from a series of individual cohorts. In line with previous publications, to the best of our knowledge, all studies that have contributed to the current meta-analysis have complied with all relevant ethical regulations, and all participants have provided informed consent.
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).
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Footnotes
↵a These authors share senior authorship
Data Availability
The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit https://research.23andme.com/collaborate/#dataset-access for more information and to for more information and to apply to access the data. All other GWAS summary statistics are publicly available from the following websites https://www.med.unc.edu/pgc/download-results/ (PGC summary statistics) and https://datashare.is.ed.ac.uk/handle/10283/3083 (broad depression summary statistics).
https://research.23andme.com/collaborate/#dataset-access