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iPSCs and iPSC-derived cells as a model of human genetic and epigenetic variation

Author

Listed:
  • Kara Quaid

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Xiaoyun Xing

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Yi-Hsien Chen

    (Washington University School of Medicine in St. Louis)

  • Yong Miao

    (Washington University School of Medicine in St. Louis)

  • Amber Neilson

    (Washington University School of Medicine in St. Louis)

  • Vijayalingam Selvamani

    (Washington University School of Medicine in St. Louis)

  • Aaron Tran

    (Washington University in St. Louis
    Washington University in St. Louis)

  • Xiaoxia Cui

    (Washington University School of Medicine in St. Louis)

  • Ming Hu

    (Cleveland Clinic Foundation)

  • Ting Wang

    (Washington University in St. Louis
    Washington University in St. Louis)

Abstract

Understanding the interaction between genetic and epigenetic variation remains a challenge due to confounding environmental factors. We propose that human induced Pluripotent Stem Cells (iPSCs) are an excellent model to study the relationship between genetic and epigenetic variation while controlling for environmental factors. In this study, we have created a comprehensive resource of high-quality genomic, epigenomic, and transcriptomic data from iPSC lines and three iPSC-derived cell types (neural stem cell (NSC), motor neuron, monocyte) from three healthy donors. We find that epigenetic variation is most strongly associated with genetic variation at the iPSC stage, and that relationship weakens as epigenetic variation increases in differentiated cells. Additionally, cell type is a stronger source of epigenetic variation than genetic variation. Further, we elucidate a utility of studying epigenetic variation in iPSCs and their derivatives for identifying important loci for GWAS studies and the cell types in which they may be acting.

Suggested Citation

  • Kara Quaid & Xiaoyun Xing & Yi-Hsien Chen & Yong Miao & Amber Neilson & Vijayalingam Selvamani & Aaron Tran & Xiaoxia Cui & Ming Hu & Ting Wang, 2025. "iPSCs and iPSC-derived cells as a model of human genetic and epigenetic variation," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56569-4
    DOI: 10.1038/s41467-025-56569-4
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    1. Helena Kilpinen & Angela Goncalves & Andreas Leha & Vackar Afzal & Kaur Alasoo & Sofie Ashford & Sendu Bala & Dalila Bensaddek & Francesco Paolo Casale & Oliver J. Culley & Petr Danecek & Adam Faulcon, 2017. "Common genetic variation drives molecular heterogeneity in human iPSCs," Nature, Nature, vol. 546(7658), pages 370-375, June.
    2. Zijuan Li & Yuyun Zhang & Ci-Hang Ding & Yan Chen & Haoyu Wang & Jinyu Zhang & Songbei Ying & Meiyue Wang & Rongzhi Zhang & Jinyi Liu & Yilin Xie & Tengfei Tang & Huishan Diao & Luhuan Ye & Yili Zhuan, 2023. "LHP1-mediated epigenetic buffering of subgenome diversity and defense responses confers genome plasticity and adaptability in allopolyploid wheat," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Zhong-Wei Du & Hong Chen & Huisheng Liu & Jianfeng Lu & Kun Qian & CindyTzu-Ling Huang & Xiaofen Zhong & Frank Fan & Su-Chun Zhang, 2015. "Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells," Nature Communications, Nature, vol. 6(1), pages 1-9, May.
    4. Yukinori Okada & Di Wu & Gosia Trynka & Towfique Raj & Chikashi Terao & Katsunori Ikari & Yuta Kochi & Koichiro Ohmura & Akari Suzuki & Shinji Yoshida & Robert R. Graham & Arun Manoharan & Ward Ortman, 2014. "Genetics of rheumatoid arthritis contributes to biology and drug discovery," Nature, Nature, vol. 506(7488), pages 376-381, February.
    5. Joshua Chiou & Ryan J. Geusz & Mei-Lin Okino & Jee Yun Han & Michael Miller & Rebecca Melton & Elisha Beebe & Paola Benaglio & Serina Huang & Katha Korgaonkar & Sandra Heller & Alexander Kleger & Seba, 2021. "Interpreting type 1 diabetes risk with genetics and single-cell epigenomics," Nature, Nature, vol. 594(7863), pages 398-402, June.
    6. Ekamper, P. & van Poppel, F. & Stein, A.D. & Lumey, L.H., 2014. "Independent and additive association of prenatal famine exposure and intermediary life conditions with adult mortality between age 18–63 years," Social Science & Medicine, Elsevier, vol. 119(C), pages 232-239.
    7. Helena Kilpinen & Angela Goncalves & Andreas Leha & Vackar Afzal & Kaur Alasoo & Sofie Ashford & Sendu Bala & Dalila Bensaddek & Francesco Paolo Casale & Oliver J. Culley & Petr Danecek & Adam Faulcon, 2017. "Correction: Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs," Nature, Nature, vol. 546(7660), pages 686-686, June.
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