Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy

Abstract

Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e−8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays

“…It has previously been demonstrated that systemic administration of all- trans retinoic acid depletes serotonin by over 40% in the rat brain 94 , supporting the serotonin system as a convergent target of retinoid-regulated pathways. As GWAS of MDD begins to explore severe, treatment-refractory cases 7 , it will be interesting to see whether associated variation still shows such convergence, as treatment-resistant depression (generally, non-response to two or more classes of antidepressant) effectively signifies non-response to multiple serotonergic agents.…”

“…Family studies have demonstrated that MDD risk is at least 30% heritable 5,6 . More recently, genome-wide association studies (GWASes) have demonstrated similar estimates for severe MDD 7 , and have helped narrow in on associated single nucleotide polymorphisms (SNPs) [8][9][10][11][12] , a tantalizing entry point for understanding the biology of MDD. However, GWAS studies do not identify causal variants, but rather implicate wider co-inherited regions consisting of many SNPs in linkage disequilibrium (LD).…”

Validity of diagnoses, treatment dates, and rating scales in the Swedish national quality register for electroconvulsive therapy

“…Data from the Q-ECT have been used in several studies [9,19,20]. For these studies to produce reliable and useable results, it is important that the data source is valid.…”

The moving target of psychiatric diagnosis

“…7,10 Conversely, a recent study of the genetics of patients with major depressive disorder treated with elec troconvulsive therapy (ECT) -arguably a much more severe and more specific diagnosis -yielded SNP heritability about 4 times greater than a standard genomewide association study of major depression. 11 In addition to the core psychiatric diagnosis, other fea tures come into play. For instance, while structural brain imaging studies of bipolar disorder found reproducible dif ferences from healthy unaffected individuals, it appears that some of the findings are not due to the disorder itself, but rather are secondary to metabolic factors such as obesity or insulin resistance that are frequently comorbid with severe mental illness.…”