Journal article
The genetics of severe depression
Molecular psychiatry, Vol.30(3), pp.1117-1126
03/2025
DOI: 10.1038/s41380-024-02731-1
PMID: 39406997
Abstract
Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.
Details
- Title: Subtitle
- The genetics of severe depression
- Creators
- Clio E Franklin - Johns Hopkins University School of MedicineEric Achtyes - Western Michigan UniversityMurat Altinay - Cleveland ClinicKala Bailey - The University of Texas Southwestern Medical CenterMahendra T Bhati - Stanford UniversityBrent R Carr - University of Florida Health Science CenterSusan K Conroy - Indiana University – Purdue University IndianapolisMustafa M Husain - The University of Texas Southwestern Medical CenterKhurshid A Khurshid - University of Massachusetts Chan Medical SchoolTodd Lencz - Donald & Barbara Zucker School of Medicine at Hofstra/NorthwellWilliam M McDonald - Emory UniversityBrian J Mickey - University of UtahJames Murrough - Icahn School of Medicine at Mount SinaiSean Nestor - University of TorontoThomas Nickl-Jockschat - Center for Intervention and Research on adaptive and maladaptive brain Circuits underlying mental health (C-I-R-C), Halle-Jena-Magdeburg, Magdeburg, GermanySina Nikayin - Yale UniversityKevin Reeves - The Ohio State UniversityIrving M Reti - Johns Hopkins MedicineSalih Selek - The University of Texas Health Science Center at HoustonGerard Sanacora - Yale UniversityNicholas T Trapp - University of IowaBiju Viswanath - National Institute of Mental Health and NeurosciencesJesse H Wright - University of LouisvillePatrick Sullivan - University of North Carolina at Chapel HillPeter P Zandi - Johns Hopkins UniversityJames B Potash - Johns Hopkins Medicine
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.30(3), pp.1117-1126
- Publisher
- SPRINGERNATURE
- DOI
- 10.1038/s41380-024-02731-1
- PMID
- 39406997
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Grant note
- R01MH121545 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) R01MH121542 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) IA/CPHI/20/1/505266 / DBT India Alliance (Wellcome Trust/DBT India Alliance)
- Language
- English
- Electronic publication date
- 10/15/2024
- Date published
- 03/2025
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984736611802771
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