Genome-wide association study of treatment resistant depression highlights shared biology with metabolic traits

Treatment resistant depression (TRD), often defined by absence of symptomatic remission following at least two adequate treatment trials, occurs in roughly a third of all individuals with major depressive disorder (MDD). Prior work has suggested a significant common variant genetic component of liability to TRD, with heritability estimates of 8% when comparing to non-treatment resistant MDD. Despite this evidence of heritability, no replicated genetic loci have been identified and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. Using electroconvulsive therapy (ECT) as a surrogate for TRD, we applied standard machine learning methods to electronic health record (EHR) data to derive predicted probabilities of receiving ECT. We applied these probabilities as a quantitative trait in a genome-wide association study (GWAS) over 154,433 genotyped patients across four large biobanks. With this approach, we demonstrate heritability ranging from 2% to 4.2% and significant genetic overlap with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits and body mass index. We identify two genome-wide significant loci, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by National Institutes of Mental Health grants R01MH116269 (DMR, CGW), R01MH121455 (DMR, CGW), R01MH116270 (DMR, CGW, RHP) and R01MH123804 (RHP), and National Institute of General Medical Sciences grant 5T32GM007347 (JK). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center's BioVU, which is supported by institutional funding, private agencies and federal grants. These include the NIH-funded Shared Instrumentation Grant S10RR025141, and CTSA grants UL1TR002243, UL1TR000445 and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962 and R01HD074711; and additional funding sources listed at . We thank Mass General Brigham Biobank for providing samples, genomic data, and health information data. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, Nashville, TN. Genotyping data from the RGC-GHS DiscovEHR collaboration was generated by the Regeneron Genetics center. This research is also based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award #MVP006. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. This study was also supported by the National Institutes of Health (NIH), Bethesda, MD under award numbers K08MH122911 (GV), R01MH125246, R01AG067025, U01MH116442, R01MH109677 (PR), and by the Veterans Affairs Merit grants BX002395 and BX004189 (PR). This study has also been funded in part by the Brain & Behavior Research Foundation via the 2020 NARSAD Young Investigator Grant #29350 (GV). ### 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 committee/IRB of the Vanderbilt University Medical Center gave ethical approval for this work (IRB# 181297) 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Summary statistics files and code used to generate data and figures are available in .