Genome-wide association meta-analysis and rare copy number variant analysis of treatment-resistant depression

Treatment-resistant depression (TRD), defined as major depressive disorder (MDD) with multiple failed responses to antidepressant treatments, has been suggested to be heritable, but identifying its genetic component is challenging. Using a restrictive TRD definition based on antidepressant medication followed by electroconvulsive therapy (ECT), which may represent a severe subset of TRD cases, we investigated both common variants and rare copy number variations (CNVs) associated with a) TRD risk (2 062 TRD vs. 441 037 healthy controls) and b) treatment resistance in MDD (2 062 TRD vs. 38 544 non-TRD) across three Nordic countries. We observed a significant SNP-based heritability for TRD risk at 26% (SE = 5%). Genome-wide association analysis identified one locus on chromosome 3 (intronic region of SPATA16) for TRD risk and one suggestive locus for treatment resistance in MDD. TRD risk showed positive genetic correlations (r_g) with other psychiatric disorders, with notably r_g with bipolar disorder (0.86, SE = 0.20) and schizophrenia (0.57, SE = 0.13), as well as a negative r_g with intelligence (-0.13, SE = 0.07). Analyses using PRS showed that TRD had higher common-variant burdens of various psychiatric disorders compared to non-TRD. Furthermore, TRD carried a higher CNV deletion burden in total and average lengths than healthy controls or non-TRD cases and was associated with a group of 54 known neuropsychiatric CNVs (ORs = 1.74-2.86). Given that our definition of TRD involves the use of ECT, our findings may reflect a severe form of treatment resistance. This work adds evidence on a genetic basis and provides insights into the genetic architecture of TRD, underscoring the need for further genomic research into this 'difficult-to-treat' condition.