Department of Psychiatry and Biobehavioral Sciences, Billy and Audrey Wilder Endowed Chair in Psychiatry and Neuroscience, Center for Neurobehavioral Genetics, 695 Charles E. Young Drive South, 3357B Gonda, Box 951761, Los Angeles, CA, 90095-1761, USA.
Mol Psychiatry. 2023 Jun;28(6):2254-2265. doi: 10.1038/s41380-023-01957-9. Epub 2023 Jan 26.
The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.
重度抑郁症（MDD）的遗传剖析是精神遗传学的成功案例之一，全基因组关联研究（GWAS）确定了 178 个遗传风险位点，并提出了 200 多个候选基因。然而，GWAS 结果来自于对队列的分析，其中大多数病例是通过最低表型诊断的，这种方法特异性较低。我回顾了一些数据，这些数据表明，MDD 存在一个很大的遗传成分，这是最低表型策略无法触及的，而且通过最低表型方法确定的大多数遗传风险位点不太可能是 MDD 风险位点。我表明，创造性地使用生物库数据、新颖的推断方法，结合更多的访谈诊断病例，可以确定与情绪、神经植物性和认知变化的阵发性严重波动有关的位点，这些变化是 MDD 的核心。此外，关于 MDD 的性质和原因的新理论，借鉴了神经科学和心理学的进展，可以为如何最好地解释和利用遗传图谱结果提供依据。
