PDF(Sci-hub)
Abstract：
Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.
摘要：
通过基因表达和可变剪接数量性状基因座（e/sQTL）分析来解释神经精神疾病和大脑相关性状的非编码风险基因座的功能通常在大量死后的成年组织中进行。然而,遗传风险位点富含在新皮质分化过程中活跃的调节元件，风险变异的调节作用可能被块状组织的异质性所掩盖。这里,我们映射e/sQTL，以及代表两个主要发育阶段的培养细胞中的等位基因特异性表达，原代人类神经祖细胞（n=85）及其分选的神经元后代（n=74），识别在发育中的皮质壁或成人皮质中未检测到的许多基因座。通过全转录组关联使用共定位和遗传归因，我们揭示了在新皮质分化过程中活跃的脑相关性状的潜在风险的细胞类型特异性调节机制.具体来说,我们确定了CENPW的祖先特异性eQTL与皮层表面积和教育程度的常见变异关联共同定位.
