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Kasela, S.* ; Aguet, F.* ; Kim-Hellmuth, S. ; Brown, B.C.* ; Nachun, D.C.* ; Tracy, R.P.* ; Durda, P.* ; Liu, Y.* ; Taylor, K.D.* ; Johnson, W.C.* ; van Den Berg, D.* ; Gabriel, S.* ; Gupta, N.* ; Smith, J.D.* ; Blackwell, T.W.* ; Rotter, J.I.* ; Ardlie, K.G.* ; Manichaikul, A.* ; Rich, S.S.* ; Barr, R.G.* ; Lappalainen, T.*

Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

Am. J. Hum. Genet. 111, 133-149 (2024)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Methylation ; Cell-type Composition ; Gene Expression ; Gene-environment Interaction ; Interaction Qtl; Integrative Analysis; Expression; Methylation; Disease; Innate; System; Risk; Loci; Eqtl
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 111, Issue: 1, Pages: 133-149 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506700-001
Grants NHLBI
NIH's National Institute of General Medical Sciences
NHGRI
National Institute of Mental Healthof the NIH
NIH's National Human Genome Research Institute (NHGRI)
Deutsche Forschungsgemeinschaft
Helmholtz Young Investigator grant
Marie-Sk1odowska Curie fellowship H2020 grant
National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH)
DOI 10.1016/j.ajhg.2023.11.013
WOS ID 001154145300001
Scopus ID 85181088634
PubMed ID 38181730
Erfassungsdatum 2024-01-07
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