Dissecting genotype-specific effects of disease-associated genetic variants

  • iScience. 2026 Jun 1;29(6):116143. doi: 10.1016/j.isci.2026.116143.
Sophie L Farrow  1  2  3 ,  Sreemol Gokuladhas  1 ,  Izlem Su Akan  4 ,  Denis Nyaga  1 ,  Antony A Cooper  5  6 ,  Ralph Stefan Grand  4 ,  Justin M O'Sullivan  1  5  7  8
Affiliations
  • 1. Liggins Institute, The University of Auckland, Auckland 1023, New Zealand.
  • 2. Oxford Parkinson's Disease Centre and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QU, UK.
  • 3. Kavli Institute for Neuroscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
  • 4. Centre for Molecular Biology of Heidelberg University (ZMBH), University of Heidelberg, 69120 Heidelberg, Germany.
  • 5. Australian Parkinsons Mission, Garvan Institute of Medical Research, Sydney, NSW, Australia.
  • 6. St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
  • 7. Singapore Institute for Clinical Sciences, Agency for Science Technology and Research, Singapore, Singapore.
  • 8. MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK.
PMID: 42291199 DOI: 10.1016/j.isci.2026.116143
Abstract

Non-coding variants associated with complex disease can shape gene regulatory networks across multiple genomic loci and cellular contexts. Here, we investigated the functional impact of the Parkinson-disease-associated variant rs11610045 using an isogenic induced pluripotent stem cell model. Using CRISPR-Cas9 editing and reversal, we generated matched clones carrying either the A|A or G|G genotype, enabling controlled comparison of allele-specific effects. We identified widespread genotype-dependent regulation of distal genes, including THBS1 and PDGFB. Affinity purification followed by mass spectrometry revealed differential binding of regulatory proteins to the G|G allele, including the transcription factor TCF7L1. Differentiation into cortical neurons demonstrated context-dependent effects, with 24 genes differentially expressed and PAX5 consistently altered across developmental stages. Together, these findings link a non-coding disease-associated variant to coordinated changes in gene expression and protein binding, support trans-acting mechanisms underlying regulatory variation, and provide a generalizable framework for dissecting disease-associated loci in human cellular models.

Keywords
Clinical neuroscience; Human genetics; Non-infectious disease.
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