Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, and the Harvard Institute for Stem Cell Biology, Harvard University, Cambridge, MA, 02138, USA.
Nat Commun. 2022 Jun 27;13(1):3690. doi: 10.1038/s41467-022-31436-8.
It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.
目前尚不清楚 22q11.2 缺失如何导致精神疾病。为了研究这一点，我们从缺失携带者和对照者中生成诱导多能干细胞，并利用 CRISPR/Cas9 将杂合缺失引入对照细胞系。在这里，我们表明，在分化为神经祖细胞后，缺失以顺式作用改变与神经发育障碍风险相关的转录本的丰度，包括自闭症的常见和罕见变体。为了了解缺失如何导致这些变化，我们定义了最佳解释基因表达改变的最小蛋白质-蛋白质相互作用网络。我们发现 22q11.2 中的许多基因在突触前、蛋白酶体和 JUN/FOS 转录途径中相互作用。我们的研究结果表明，22q11.2 缺失影响可能与精神疾病风险基因座汇集的基因，以影响每个缺失携带者的疾病表现。
