A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder. A candidate causal variant underlying both enhanced cognitive performance and increased risk of bipolar disorder

Bipolar disorder is a highly heritable mental illness, but the relevant genetic variants and molecular mechanisms are largely unknown. Recent GWASs have identified an intergenic region associated with both cognitive performance and bipolar disorder. This region contains dozens of putative fetal brain-specific enhancers and is located ~0.7 Mb upstream of the neuronal transcription factor POU3F2. We identified a candidate causal variant, rs77910749, that falls within a highly conserved putative enhancer, LC1. This human-specific variant is a single-base deletion in a PAX6 binding site and is predicted to be functional. We hypothesized that rs77910749 alters LC1 activity and hence POU3F2 expression during neurodevelopment. Indeed, transgenic reporter mice demonstrated LC1 activity in the developing cerebral cortex and amygdala. Furthermore, ex vivo reporter assays in embryonic mouse brain and human iPSC-derived cerebral organoids revealed increased enhancer activity conferred by the variant. To probe the in vivo function of LC1, we deleted the orthologous mouse region, which resulted in amygdala-specific changes in Pou3f2 expression. Lastly, ‘humanized’ rs77910749 knock-in mice displayed behavioral defects in sensory gating, an amygdala-dependent endophenotype seen in patients with bipolar disorder. Our study suggests a molecular mechanism underlying the long-speculated link between enhanced cognitive performance and neuropsychiatric disease. Overall design: mRNA-seq in mouse brain

双相情感障碍（Bipolar disorder）是一种遗传度极高的精神疾病，但其相关遗传变异与分子机制仍未明确。近期的全基因组关联研究（Genome-Wide Association Studies, GWAS）已鉴定出一个同时与认知表现及双相情感障碍相关的基因间区。该区域包含数十个推定的胎儿脑特异性增强子，且位于神经元转录因子POU3F2上游约0.7 Mb处。我们鉴定出候选致病变异rs77910749，其位于高度保守的推定增强子LC1内部。这一人类特异性变异为PAX6结合位点内的单碱基缺失，且被预测具有功能活性。我们假设rs77910749可在神经发育过程中改变LC1的活性，进而影响POU3F2的表达。

确实，转基因报告小鼠实验证实LC1在发育中的大脑皮层与杏仁核中具有活性。此外，在小鼠胚胎脑组织与人类诱导多能干细胞（iPSC）来源的大脑类器官中开展的离体报告基因实验显示，该变异可增强增强子活性。为探究LC1的体内功能，我们敲除了小鼠的同源区域，这导致了杏仁核中Pou3f2表达的特异性改变。最后，携带“人源化”rs77910749的敲入小鼠表现出感觉门控行为缺陷，而感觉门控是双相情感障碍患者中观察到的、依赖于杏仁核的内表型。

本研究为长期以来推测的“认知表现提升与神经精神疾病之间的关联”提供了潜在的分子机制。实验整体设计：小鼠脑组织mRNA测序。