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Hawe, J. ; Wilson, R. ; Schmid, K. ; Zhou, L.* ; Lakshmanan, L.N.* ; Lehne, B.C.* ; Kühnel, B. ; Scott, W.R.* ; Wielscher, M.* ; Yew, Y.W.* ; Baumbach, C. ; Lee, D.P.* ; Marouli, E.* ; Bernard, M.* ; Pfeiffer, L. ; Matias-Garcia, P.R. ; Autio, M.I.* ; Bourgeois, S.* ; Herder, C.* ; Karhunen, V.* ; Meitinger, T. ; Prokisch, H. ; Rathmann, W.* ; Roden, M.* ; Sebert, S.* ; Shin, J.* ; Strauch, K. ; Zhang, W.* ; Tan, W.L.W.* ; Hauck, S.M. ; Merl-Pham, J. ; Grallert, H. ; Barbosa, E.G.V. ; Illig, T.* ; Peters, A. ; Paus, T.* ; Pausova, Z.* ; Deloukas, P.* ; Foo, R.S.Y.* ; Jarvelin, M.R.* ; Kooner, J.S.* ; Loh, M.* ; Heinig, M. ; Gieger, C. ; Waldenberger, M. ; Chambers, J.C.*

Genetic variation influencing DNA methylation provides insights into molecular mechanisms regulating genomic function.

Nat. Genet. 54, 18–29 (2022)
Postprint Forschungsdaten DOI PMC
Open Access Green
We determined the relationships between DNA sequence variation and DNA methylation using blood samples from 3,799 Europeans and 3,195 South Asians. We identify 11,165,559 SNP-CpG associations (methylation quantitative trait loci (meQTL), P < 10-14), including 467,915 meQTL that operate in trans. The meQTL are enriched for functionally relevant characteristics, including shared chromatin state, High-throuhgput chromosome conformation interaction, and association with gene expression, metabolic variation and clinical traits. We use molecular interaction and colocalization analyses to identify multiple nuclear regulatory pathways linking meQTL loci to phenotypic variation, including UBASH3B (body mass index), NFKBIE (rheumatoid arthritis), MGA (blood pressure) and COMMD7 (white cell counts). For rs6511961 , chromatin immunoprecipitation followed by sequencing (ChIP-seq) validates zinc finger protein (ZNF)333 as the likely trans acting effector protein. Finally, we used interaction analyses to identify population- and lineage-specific meQTL, including rs174548 in FADS1, with the strongest effect in CD8+ T cells, thus linking fatty acid metabolism with immune dysregulation and asthma. Our study advances understanding of the potential pathways linking genetic variation to human phenotype.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Epigenome-wide Association; Rheumatoid-arthritis; Expression; Blood; Reveals; Links; Identification; Tocilizumab; Signatures; Enhancers
Sprache englisch
Veröffentlichungsjahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Zeitschrift Nature Genetics
Quellenangaben Band: 54, Heft: , Seiten: 18–29 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Computational Biology (ICB)
Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
Institute of Genetic Epidemiology (IGE)
CF Metabolomics & Proteomics (CF-MPC)
POF Topic(s) 30202 - Environmental Health
30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30203 - Molecular Targets and Therapies
Forschungsfeld(er) Genetics and Epidemiology
Enabling and Novel Technologies
PSP-Element(e) G-504091-001
G-504091-004
G-553500-001
G-503800-001
G-500700-001
G-503292-001
G-504100-001
G-505700-001
G-504091-002
G-504000-010
Förderungen MOH | National Medical Research Council (NMRC)
DOI 10.1038/s41588-021-00969-x
WOS ID WOS:000737754100002
Scopus ID 85122284960
PubMed ID 34980917
Erfassungsdatum 2022-02-08
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