Department of Biomedicine, Aarhus University, Aarhus, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Nat Med. 2023 Jul;29(7):1832-1844. doi: 10.1038/s41591-023-02352-1. Epub 2023 Jul 18.
Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.
抑郁症是一种常见的精神障碍，也是全球导致残疾的主要原因。在这里，我们对六个数据集进行了全基因组关联研究荟萃分析，包括超过 130 万人（371184 人患有抑郁症），并确定了 243 个风险位点。总的来说，有 64 个新的位点，包括编码谷氨酸和 GABA 受体的基因，这些基因是抗抑郁药物的靶点。与功能基因组学数据的交集优先考虑了可能的因果基因，并揭示了新的产前 GABA 能神经元、星形胶质细胞和少突胶质细胞谱系的富集。我们发现抑郁症具有高度多基因性，约有 11700 个变异解释了单核苷酸多态性遗传率的 90%，估计当考虑一致和不一致的变异时，超过 95%的其他精神障碍（焦虑症、精神分裂症、双相情感障碍和注意缺陷多动障碍）的风险变异都在影响抑郁症风险，几乎所有的抑郁症风险变异都影响着教育程度。此外，抑郁症的遗传风险与复杂认知领域的受损有关。我们剖析了遗传和临床异质性，揭示了抑郁症亚组中不同的多基因结构，并证明了具有最高多基因负担的抑郁症病例中复发和精神共病的绝对风险显著增加，且存在相当大的性别差异。与具有最低多基因负担的病例和背景人群相比，风险分别高出 5 倍和 32 倍。这些结果加深了我们对抑郁症生物学基础、疾病进展的理解，并为精准医疗治疗方法提供了信息。
