Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

双相情感障碍 (BD) 和肥胖症是高度共病的。我们之前针对体重指数 (BMI) 的影响对 BD 风险进行了全基因组关联研究 (GWAS)，该研究在编码转录因子 7 的基因中发现了全基因组显着的单核苷酸多态性 (SNP)，例如2 ( TCF7L2 )。然而，TCF7L2在中枢神经系统 (CNS) 中的分子功能及其在 BD 和 BMI 相互作用中的可能作用仍不清楚。在本研究中，我们通过研究人诱导多能干细胞 (hiPSC) 衍生的星形胶质细胞、高度表达TCF7L2的细胞来证明在 CNS 中，BD-BMI GWAS 风险 SNP 与糖皮质激素依赖性抑制先前未表征的 TCF7L2 转录变体的表达有关。该转录本是一种长链非编码 RNA (lncRNA-TCF7L2)，它在中枢神经系统中高表达，但在参与新陈代谢的外周组织（例如肝脏和胰腺）中不高表达。在星形胶质细胞中，lncRNA-TCF7L2 的敲低导致亲本基因TCF7L2的表达降低，以及一系列与胰岛素信号和糖尿病有关的基因表达的改变。我们还通过整合 TCF7L2 敲低后的 RNA 测序数据与 TCF7L2 染色质免疫沉淀测序 (ChIP-seq) 数据，研究了 TCF7L2 在 hiPSC 衍生的星形胶质细胞中的功能。这些研究表明，TCF7L2 直接调节了一系列 BD 风险基因。总之，这些结果支持基于 CNS 的 BD-BMI 遗传风险机制的存在，该机制基于糖皮质激素依赖性表达数量性状基因座，可调节新型 TCF7L2 非编码转录物的表达。