Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Identifies Novel Risk Genes for Schizophrenia.

Multiple integrative studies have been performed to identify the potential target genes of the non-coding schizophrenia (SCZ) risk variants. However, all the integrative studies used expression quantitative trait loci (eQTL) data from bulk tissues. Considering the cell type-specific regulatory effect of many genetic variants, it is important to conduct integrative studies using cell type-specific eQTL data. Here, we conduct a Mendelian randomization (MR) study by integrating genome-wide associations of SCZ (74,776 cases and 101,023 controls) and eQTL data (N = 215) from dopaminergic neurons, which were differentiated from human-induced pluripotent stem cell (iPSC) lines. For eQTL from young post-mitotic dopaminergic neurons (differentiation of iPSC for 30 days, D30), we identified 34 genes whose genetically regulated expression in dopaminergic neurons may have a causal role in SCZ. Among which, ARL3 showed the most significant associations with SCZ. For eQTL from more mature dopaminergic neurons (D52), we identified 37 potential SCZ causal genes, and ARL3 and GNL3 showed the most significant associations. Only 12 genes showed significant associations with SCZ in both D30 and D52 eQTL datasets, indicating the time point-specific genetic regulatory effects in young post-mitotic dopaminergic neurons and more mature dopaminergic neurons. Comparing the results from dopaminergic neurons with bulk brain tissues prioritized 2 high-confidence risk genes, including DDHD2 and GALNT10. Our study identifies multiple risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in SCZ. Further mechanistic investigation will provide pivotal insights into SCZ pathophysiology.