Franklin Clio E, Achtyes Eric, Altinay Murat, Bailey Kala, Bhati Mahendra T, Carr Brent R, Conroy Susan K, Husain Mustafa M, Khurshid Khurshid A, Lencz Todd, McDonald William M, Mickey Brian J, Murrough James, Nestor Sean, Nickl-Jockschat Thomas, Nikayin Sina, Reeves Kevin, Reti Irving M, Selek Salih, Sanacora Gerard, Trapp Nicholas T, Viswanath Biju, Wright Jesse H, Sullivan Patrick, Zandi Peter P, Potash James B
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Psychiatry, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
Mol Psychiatry. 2025 Mar;30(3):1117-1126. doi: 10.1038/s41380-024-02731-1. Epub 2024 Oct 15.
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.
重度抑郁症（MDD）的全基因组关联研究（GWAS）最近已达到极大的样本量，并产生了大量全基因组显著位点。由于这些研究中许多的确定和评估方法，其中一些位点似乎与烦躁不安而非MDD相关，这可能会降低研究结果的临床相关性。MDD的GWAS的另一种方法是关注MDD最严重的形式，希望这将富集具有更大效应的位点，使其识别变得合理，并提供可能更具临床可操作性的结果。在这里，我们通过使用严重程度的临床标志物来综述重度抑郁症的遗传学，这些标志物包括：发病年龄、复发情况、损害程度以及ECT治疗。有证据表明，在复发性和早发性疾病以及严重功能损害中，基于家族和单核苷酸多态性（SNP）的遗传力估计值增加。已经针对严重形式的MDD进行了GWAS，并确定了一些全基因组位点。还进行了几项全外显子组测序研究，确定了相关的罕见变异。尽管这些发现尚未得到严格重复，但在严重MDD表型中观察到的遗传力升高表明，对该人群样本进行额外的全基因组研究具有价值。现在的挑战是生成一个具有一致表型分型的足够大的队列，这将允许进行仔细且可靠的分类和区分。我们目前正在我们的全球50个站点的基因-ECT联盟中推行这样一种策略。
