Systems (epi)genetics to study the basis of complex traits and diseases
Maya Kasowski*, Sofia Kyriazopoulou-Panagiotopoulou,*, Fabian Grubert,*, Judith B. Zaugg,*, Anshul Kundaje*, Yuling Liu, Alan P. Boyle, Qiangfeng Cliff Zhang, Fouad Zakharia, Damek V. Spacek, Jingjing Li, Dan Xie, Anthony Olarerin-George, Lars M. Steinmetz, John B. Hogenesch, Manolis Kellis, Serafim Batzoglou, Michael Snyder
* These authors contributed equally to this study.The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans.