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Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects
New York Genome Center, New York, NY, USA; Department of Systems Biology, Columbia University, New York, NY, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
New York Genome Center, New York, NY, USA; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital LMU Munich, Munich, Germany; Computational Health Center, Institute of Translational Genomics, Helmholtz Munich, Neuherberg, Germany.
New York Genome Center, New York, NY, USA; Data Science Institute, Columbia University, New York, NY, USA.
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2024 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 111, no 1, p. 133-149Article in journal (Refereed) Published
Abstract [en]

Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.

Place, publisher, year, edition, pages
Elsevier BV , 2024. Vol. 111, no 1, p. 133-149
Keywords [en]
cell-type composition, DNA methylation, gene expression, gene-environment interaction, interaction QTL
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:kth:diva-342191DOI: 10.1016/j.ajhg.2023.11.013ISI: 001154145300001PubMedID: 38181730Scopus ID: 2-s2.0-85181088634OAI: oai:DiVA.org:kth-342191DiVA, id: diva2:1827889
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QC 20240115

Available from: 2024-01-15 Created: 2024-01-15 Last updated: 2025-12-05Bibliographically approved

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Lappalainen, Tuuli

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