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） 最近实现了极大的样本量，并产生了大量全基因组显着基因座。由于许多这些研究的确定和评估方法，其中一些基因座似乎与烦躁症有关，而不是与 MDD 有关，这可能会降低研究结果的临床相关性。MDD GWAS 的另一种方法是关注最严重的 MDD 形式，希望这将丰富具有更大影响的基因座，使其识别合理，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回顾严重抑郁症的遗传学，包括：发病年龄、复发、损伤程度和 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伤中，基于家族和基于单核苷酸多态性 （SNP） 的遗传性估计增加。已经对严重形式的 MDD 进行了 GWAS，并已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，鉴定了相关的罕见变异。尽管这些发现尚未被严格复制，但在严重的 MDD 表型中观察到的遗传性升高表明对来自该人群的样本进行额外的全基因组询问的价值。现在的挑战是生成一个足够规模的队列，具有一致的表型，这将允许进行仔细和稳健的分类和区分。我们目前正在全球 50 个站点的 Gen-ECT-ics 联盟中寻求这样的战略。