Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits

Abstract

Objective: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, 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. The objective of this study was to perform a well-powered genetic study of TRD.

Methods: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks.

Results: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications.

Conclusions: 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.

Keywords: Depressive Disorders; Electroconvulsive Therapy (ECT); Genetics/Genomics; Major Depressive Disorder; Treatment-Resistant Depression.

FIGURE 1.. Schematic of the TRD clinical model generation and the genome-wide association study of the quantitative ECT prediction scores^a

^aAs shown in panel A, TRD case subjects and non-TRD MDD control subjects were extracted from EHRs at VUMC and MGB. In panel B, prediction models leveraging clinical data from the EHR were trained separately on VUMC and MGB data and applied to four independent data sets to generate probabilities, and in panel C, probabilities were used as quantitative TRD phenotypes to perform two GWASs of TRD in 154,443 individuals. CPT=Current Procedural Terminology; ECT=electroconvulsive therapy; EHR=electronic health record; GWAS=genome-wide association study; MDD=major depressive disorder; MGB=Mass General Brigham; PRS=polygenic risk score; TRD=treatment-resistant depression; VUMC=Vanderbilt University Medical Center.

FIGURE 2.. Manhattan plots of TRD meta-analyses for MGB and VUMC^a

^a MGB=Mass General Brigham; TRD=treatment-resistant depression; VUMC=Vanderbilt University Medical Center.

FIGURE 3.. Forest plot of the genome-wide significant loci rs56313538 on chromosome 16 and rs133082 on chromosome 22^a

^a The chromosome 16 locus is significantly associated with the MGB TRD meta-analysis (TRD_MGB), and the chromosome 22 locus is significantly associated with both the MGB and VUMC TRD meta-analyses (TRD_VUMC). Neither locus was significantly associated in two other TRD studies using different TRD definitions: a GWAS of TRD based on antidepressant prescriptions in the UK Biobank (11) (TRD_UKB) and a GWAS of TRD of ECT case subjects against healthy control subjects from the Predictors for ECT (PREFECT) study (31) (TRD_PREFECT). The points indicate the log odds ratio, and the error bars show the standard error; the p value of association with each phenotype is shown above the error bars. ECT=electroconvulsive therapy; GHS=Geisinger Health System; GWAS=genome-wide association study; MGB=Mass General Brigham; MVP=Million Veteran Program; TRD=treatment-resistant depression; VUMC=Vanderbilt University Medical Center.

FIGURE 4.. Genetic correlations of MGB TRD meta-analysis (TRD_MGB) and VUMC TRD meta-analysis (TRD_VUMC) with psychiatric and nonpsychiatric traits^a

^a Unfilled points indicate genetic correlations that did not pass the Bonferroni-corrected significance p threshold of <1.72×10⁻³ (29 traits tested). Error bars represent the standard error; p values shown above the error bars indicate significance after Bonferroni correction. Traits in boldface showed significant differences in genetic correlations between the two meta-analyses. Source GWASs of psychiatric and nonpsychiatric traits are listed in Table S7 in the online supplement. ADHD=attention deficit hyperactivity disorder; AUDIT=Alcohol Use Disorders Identification Test; AUDIT-C=AUDIT-Consumption score; AUDIT-P=AUDIT-Problems score; AUDIT-T=AUDIT total score; BMI=body mass index; EUR=GWAS limited to samples of European ancestries; GWAS=genome-wide association study; MGB=Mass General Brigham; OCD=obsessive-compulsive disorder; PTSD=posttraumatic stress disorder; TRD=treatment-resistant depression; VUMC=Vanderbilt University Medical Center.