Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neurons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schizophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin interaction, and validated enhancer data, placing variants in the cellular context where they may modulate risk.

中文翻译：

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利用小鼠染色质数据进行遗传性富集，可以了解常见疾病的结构，并揭示皮质层对精神分裂症的影响。


全基因组关联研究表明，常见人类表型中存在数千种非编码变异。然而，它们无法直接告知疾病相关变异发挥作用的细胞环境。在这里，我们使用离散小鼠细胞群的开放染色质图谱来应对这一挑战。我们在 64 项全基因组关联研究中应用分层连锁不平衡评分回归并评估遗传性富集，重点关注精神分裂症。我们提供的证据表明，小鼠来源的人类开放染色质谱可以作为难以获得的人类细胞群的有力代理，有助于阐明一系列人类表型的常见疾病遗传性富集。我们证明，来自皮质兴奋性和抑制性神经元离散亚群的特征显着富集于精神分裂症遗传性，其中皮质 V 层兴奋性神经元的富集程度最大。我们还发现，精神分裂症和双相情感障碍之间的差异集中在皮质层 II-III、IV 和 V 以及齿状回的兴奋性神经元上。最后，我们利用这些数据对 104/177 中 177 个精神分裂症位点提名变异进行精细定位。我们将这些数据与转录因子结合位点、染色质相互作用和经过验证的增强子数据整合，将变异置于可能调节风险的细胞环境中。