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

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. 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. 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. 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.

Déclaration de conflit d'intérêts

Dr. McCoy has received support from grants to his institution from Koa Health and InterSystems, and he has received an honorarium from Springer Nature for editorial work. Dr. Perlis has served as a consultant or scientific advisory board member for Alkermes, Belle Artificial Intelligence, Burrage Capital, Circular Genomics, Genomind, and Vault Health; he serves as an associate editor for JAMA Network–Open; and he has equity in Belle Artificial Intelligence, Circular Genomics, Genomind, Psy Therapeutics, and Vault Health. Dr. Ruderfer has served on advisory boards for Alkermes and Illumina and has received research funds from PTC Therapeutics. The other authors report no financial relationships with commercial interests.