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Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

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Item Type:Article
Title:Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Creators Name:Grosche, S. and Marenholz, I. and Esparza-Gordillo, J. and Arnau-Soler, A. and Pairo-Castineira, E. and Rüschendorf, F. and Ahluwalia, T.S. and Almqvist, C. and Arnold, A. and Baurecht, H. and Bisgaard, H. and Bønnelykke, K. and Brown, S.J. and Bustamante, M. and Curtin, J.A. and Custovic, A. and Dharmage, S.C. and Esplugues, A. and Falchi, M. and Fernandez-Orth, D. and Ferreira, M.A.R. and Franke, A. and Gerdes, S. and Gieger, C. and Hakonarson, H. and Holt, P.G. and Homuth, G. and Hubner, N. and Hysi, P.G. and Jarvelin, M.R. and Karlsson, R. and Koppelman, G.H. and Lau, S. and Lutz, M. and Magnusson, P.K.E. and Marks, G.B. and Müller-Nurasyid, M. and Nöthen, M.M. and Paternoster, L. and Pennell, C.E. and Peters, A. and Rawlik, K. and Robertson, C.F. and Rodriguez, E. and Sebert, S. and Simpson, A. and Sleiman, P.M.A. and Standl, M. and Stölzl, D. and Strauch, K. and Szwajda, A. and Tenesa, A. and Thompson, P.J. and Ullemar, V. and Visconti, A. and Vonk, J.M. and Wang, C.A. and Weidinger, S. and Wielscher, M. and Sargent, C.L. and Xu, C.J. and Lee, Y.A.
Abstract:Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:12
Number:1
Page Range:6618
Date:16 November 2021
Official Publication:https://doi.org/10.1038/s41467-021-26783-x
PubMed:View item in PubMed

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