Hook Paul W, McCallion Andrew S
McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Department of Comparative and Molecular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Genome Res. 2020 Apr;30(4):528-539. doi: 10.1101/gr.256578.119. Epub 2020 Apr 17.
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.
全基因组关联研究已经在常见人类表型中发现了数千个非编码变异。然而，它们无法直接说明疾病相关变异发挥作用的细胞背景。在此，我们使用来自离散小鼠细胞群体的开放染色质图谱来应对这一挑战。我们应用分层连锁不平衡评分回归，并在64项全基因组关联研究（重点是精神分裂症）中评估遗传力富集情况。我们提供的证据表明，源自小鼠的人类开放染色质图谱可以作为难以获取的人类细胞群体的有力替代物，有助于阐明一系列人类表型中的常见疾病遗传力富集情况。我们证明，皮质兴奋性和抑制性神经元离散亚群的特征在精神分裂症遗传力方面显著富集，在皮质第V层兴奋性神经元中富集程度最高。我们还表明，精神分裂症和双相情感障碍之间的差异集中在皮质第II - III层、第IV层和第V层的兴奋性神经元以及齿状回中。最后，我们利用这些数据对177个精神分裂症位点中的变异进行精细定位，在177个位点中的104个位点中确定了变异。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在一起，将变异置于它们可能调节风险的细胞背景中。
