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


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.

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Fig. 1: Genome-wide association results.
Fig. 2: Comparison of SNP-based heritability (h2) estimates and impact of population prevalence.
Fig. 3: Genetic correlations comparing a sample with severe major depressive episodes (green, mddnarrow, and blue, mddbroad PREFECT case definitions) to a large sample of more moderate cases (orange, mdd2019, Psychiatric Genomics Consortium—Major Depressive Disorder Working Group sample excluding 23andMe) on psychiatric, neurological, and central nervous system disorders along with other traits.
Fig. 4: Genetic risk scores (GRS) in severe ECT-treated major depressive disorder (MDD) cases (PREFECT MDD) compared with more mild/moderate internet-based cognitive behavioral therapy (iCBT) MDD cases.

Data availability

Summary statistics are available for download on the Psychiatric Genomic Consortium website.


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We first thank the study participants. We also thank the staff at participating ECT-units in Danderyd, Huddinge, Hudiksvall, Sahlgrenska, Umeå, Uppsala, and Örebro for recruiting patients; the Swedish National Quality Register for ECT (Q-ECT) for providing data; and the and KI Biobank at Karolinska Institutet for professional biobank service. We thank PREFECT data collectors Marie Lundin, Birgitta Ohlander, Milka Krestelica, Radja Dawoud, Martina Wennberg, and PREFECT data manager Bozenna Illadou. The PREFECT study was funded by the Swedish foundation for Strategic Research (KF10-0039), and grants from the Swedish Research Council (2018-02653). PFS was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501), the Horizon 2020 Program of the European Union (COSYN, RIA Grant Agreement No. 610307), and US NIMH (U01 MH109528 and R01 MH077139). CMB was supported by Swedish Research Council (Vetenskapsrådet, award: 538-2013-8864) and US NIMH (R01MH120170, R01MH119084, and U01 MH109528). CR was supported by the Swedish Research Council (2018-02487) and the Swedish Research Council for Health, Working Life and Welfare (2018-00221). CCC was supported by a US Fulbright grant. YL is in part supported by a 2018 NARSAD Young Investigator Grant from the Brain & Behaviour Research Foundation and US NIMH (R01 MH123724).

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Correspondence to Patrick F. Sullivan or Mikael Landén.

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ML declares that, over the past 36 months, he has received lecture honoraria from Lundbeck pharmaceutical. PFS reports the following potentially competing financial interests. Current: Lundbeck (advisory committee, grant recipient), RBNC Therapeutics (advisory committee, stock ownership). CMB reports: Shire (grant recipient, Scientific Advisory Board member); Idorsia (consultant); Pearson (author, royalty recipient). AJ is currently employed at the Swedish Medical Products Agency, SE-75103 Uppsala, Sweden. The views expressed in this paper are the personal views of the authors and not necessarily the views of the government agency. AJ’s contribution to this work was done before he started his employment at the MPA.

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Clements, C.C., Karlsson, R., Lu, Y. et al. Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy. Mol Psychiatry 26, 2429–2439 (2021).

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