The first people's hospital of Yunnan province, Psychiatry Department, 650032, Kunming, Yunnan, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, 650223, Kunming, Yunnan, China.
Neuropsychopharmacology. 2019 Aug;44(9):1542-1551. doi: 10.1038/s41386-019-0345-4. Epub 2019 Feb 16.
Major depressive disorder (MDD) is the most prevalent mental disorder that affects more than 200 million people worldwide. Recent large-scale genome-wide association studies (GWAS) have identified multiple risk variants that show robust association with MDD. Nevertheless, how the identified risk variants confer risk of MDD remains largely unknown. To identify risk variants that are associated with gene expression in human brain and to identify genes whose expression change may contribute to the susceptibility of MDD, we systematically integrated the genetic associations from a large-scale MDD GWAS (N = 480,359) and brain expression quantitative trait loci (eQTL) data (N = 494) using a Bayesian statistical framework (Sherlock). Sherlock integrative analysis showed that FLOT1 was significantly associated with MDD (P = 6.02 × 10), suggesting that risk variants may contribute to MDD susceptibility through affecting FLOT1 expression. We further examined the expression level of FLOT1 in MDD cases and controls and found that FLOT1 was significantly upregulated in brains and peripheral blood of MDD cases compared with controls (European sample). Interestingly, we found that FLOT1 expression was also significantly upregulated in peripheral blood of first-episode drug-naive MDD cases compared with controls (P = 1.01 × 10, Chinese sample). Our study identified FLOT1 as a novel MDD risk gene whose expression level may play a role in MDD. In addition, our findings also suggest that risk variants may confer risk of MDD through affecting expression of FLOT1. Further functional investigation of FLOT1 may provide new insights for MDD pathogenesis.
重度抑郁症（MDD）是最常见的精神障碍，影响着全球超过 2 亿人。最近的大规模全基因组关联研究（GWAS）已经确定了多个与 MDD 具有强大关联的风险变异。然而，确定的风险变异如何导致 MDD 的风险仍然很大程度上未知。为了鉴定与人类大脑基因表达相关的风险变异，并鉴定表达变化可能导致 MDD 易感性的基因，我们使用贝叶斯统计框架（Sherlock）系统地整合了大规模 MDD GWAS（N=480359）和大脑表达数量性状基因座（eQTL）数据（N=494）的遗传关联。Sherlock 综合分析表明，FLOT1 与 MDD 显著相关（P=6.02×10），表明风险变异可能通过影响 FLOT1 表达导致 MDD 易感性。我们进一步检查了 MDD 病例和对照中 FLOT1 的表达水平，发现与对照组相比，MDD 病例的大脑和外周血中 FLOT1 的表达显著上调（欧洲样本）。有趣的是，我们发现与对照组相比，首次发作、未经药物治疗的 MDD 病例的外周血中 FLOT1 的表达也显著上调（P=1.01×10，中国样本）。我们的研究确定了 FLOT1 作为一个新的 MDD 风险基因，其表达水平可能在 MDD 中起作用。此外，我们的研究结果还表明，风险变异可能通过影响 FLOT1 的表达来赋予 MDD 的风险。对 FLOT1 的进一步功能研究可能为 MDD 的发病机制提供新的见解。
