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, Kunming, Yunnan 650223, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
Schizophr Bull. 2021 Aug 21;47(5):1364-1374. doi: 10.1093/schbul/sbab032.
Recent large-scale integrative analyses (including Transcriptome-Wide Association Study [TWAS] and Summary-data-based Mendelian Randomization [SMR]) have identified multiple genes whose cis-regulated expression changes may confer risk of schizophrenia. Nevertheless, expression quantitative trait loci (eQTL) data and genome-wide associations used for integrative analyses were mainly from populations of European ancestry, resulting in potential missing of pivotal biological insights in other continental populations due to population heterogeneity. Here we conducted TWAS and SMR integrative analyses using blood eQTL (from 162 subjects) and GWAS data (22 778 cases and 35 362 controls) of schizophrenia in East Asian (EAS) populations. Both TWAS (P = 2.89 × 10-14) and SMR (P = 6.04 × 10-5) analyses showed that decreased TMEM180 mRNA expression was significantly associated with risk of schizophrenia. We further found that TMEM180 was significantly down-regulated in the peripheral blood of schizophrenia cases compared with controls (P = 8.63 × 10-4 in EAS sample), and its expression was also significantly lower in the brain tissues of schizophrenia cases compared with controls (P = 1.87 × 10-5 in European sample from PsychENCODE). Functional explorations suggested that Tmem180 knockdown affected neurodevelopment, ie, proliferation and differentiation of neural stem cells. RNA sequencing showed that pathways regulated by Tmem180 were significantly enriched in brain development and synaptic transmission. In conclusion, our study provides convergent lines of evidence for the involvement of TMEM180 in schizophrenia, and highlights the potential and importance of resource integration and sharing at this big data era in bio-medical research.
最近的大规模综合分析（包括转录组关联研究 [TWAS] 和基于汇总数据的孟德尔随机化 [SMR]）已经确定了多个基因，其顺式调控表达变化可能导致精神分裂症的风险。然而，用于综合分析的表达数量性状基因座（eQTL）数据和全基因组关联主要来自欧洲血统的人群，由于人群异质性，导致其他大陆人群中潜在的关键生物学见解缺失。在这里，我们使用东亚（EAS）人群的血液 eQTL（来自 162 个个体）和精神分裂症 GWAS 数据（22778 例病例和 35362 例对照）进行了 TWAS 和 SMR 综合分析。TWAS（P=2.89×10-14）和 SMR（P=6.04×10-5）分析均表明，TMEM180 mRNA 表达降低与精神分裂症风险显著相关。我们进一步发现，与对照组相比，精神分裂症病例的外周血中 TMEM180 显著下调（在 EAS 样本中 P=8.63×10-4），并且其在精神分裂症病例的脑组织中的表达也明显低于对照组（在来自 PsychENCODE 的欧洲样本中 P=1.87×10-5）。功能探索表明，Tmem180 敲低会影响神经发育，即神经干细胞的增殖和分化。RNA 测序表明，Tmem180 调节的途径在大脑发育和突触传递中显著富集。总之，我们的研究为 TMEM180 参与精神分裂症提供了一致的证据，并强调了在这个大数据时代生物医学研究中资源整合和共享的潜力和重要性。
