Department of Translational Research in Psychiatry, Max-Planck Institute of Psychiatry, 80804 Munich, Germany.
Cells. 2020 Feb 5;9(2):366. doi: 10.3390/cells9020366.
Genome-wide association studies (GWAS) have identified an increasing number of genetic variants that significantly associate with psychiatric disorders. Despite this wealth of information, our knowledge of which variants causally contribute to disease, how they interact, and even more so of the functions they regulate, is still poor. The availability of embryonic stem cells (ESCs) and the advent of patient-specific induced pluripotent stem cells (iPSCs) has opened new opportunities to investigate genetic risk variants in living disease-relevant cells. Here, we analyze how this progress has contributed to the analysis of causal relationships between genetic risk variants and neuronal phenotypes, especially in schizophrenia (SCZ) and bipolar disorder (BD). Studies on rare, highly penetrant risk variants have originally led the field, until more recently when the development of (epi-) genetic editing techniques spurred studies on cause-effect relationships between common low risk variants and their associated neuronal phenotypes. This reorientation not only offers new insights, but also raises issues on interpretability. Concluding, we consider potential caveats and upcoming developments in the field of ESC/iPSC-based modeling of causality in psychiatric disorders.
全基因组关联研究（GWAS）已经确定了越来越多与精神疾病显著相关的遗传变异。尽管有了这些丰富的信息，但我们对哪些变异是导致疾病的原因、它们如何相互作用，甚至对它们调节的功能知之甚少。胚胎干细胞（ESCs）的出现和患者特异性诱导多能干细胞（iPSCs）的出现为研究与疾病相关的活细胞中的遗传风险变异提供了新的机会。在这里，我们分析了这一进展如何有助于分析遗传风险变异与神经元表型之间的因果关系，特别是在精神分裂症（SCZ）和双相情感障碍（BD）中。对罕见的、高外显率风险变异的研究最初引领了该领域，直到最近，（表观）遗传编辑技术的发展促使人们研究常见低风险变异与其相关的神经元表型之间的因果关系。这种重新定位不仅提供了新的见解，而且还提出了关于可解释性的问题。最后，我们考虑了基于 ESC/iPSC 的精神疾病因果关系建模领域的潜在注意事项和未来发展。
