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

Sarah Grosche, Ingo Marenholz, Jorge Esparza-gordillo, Aleix Arnau-soler, Erola Pairo-castineira, Franz Rüschendorf, Tarunveer S. Ahluwalia, Catarina Almqvist, Andreas Arnold, Hansjörg Baurecht, Hans Bisgaard, Klaus Bønnelykke, Sara J. Brown, Mariona Bustamante, John A. Curtin, Shyamali C. Dharmage, Ana Esplugues, Mario Falchi, Dietmar Fernandez-orth, Manuel A. R. FerreiraAndre Franke, Sascha Gerdes, Christian Gieger, Hakon Hakonarson, Patrick G. Holt, Georg Homuth, Norbert Hubner, Pirro G. Hysi, Marjo-riitta Jarvelin, Robert Karlsson, Gerard H. Koppelman, Susanne Lau, Manuel Lutz, Patrik K. E. Magnusson, Guy B. Marks, Martina Müller-nurasyid, Markus M. Nöthen, Lavinia Paternoster, Craig E. Pennell, Annette Peters, Konrad Rawlik, Colin F. Robertson, Elke Rodriguez, Sylvain Sebert, Angela Simpson, Patrick M. A. Sleiman, Marie Standl, Dora Stölzl, Konstantin Strauch, Agnieszka Szwajda, Albert Tenesa, Vilhelmina Ullemar, Alessia Visconti, Judith M. Vonk, Carol A. Wang, Stephan Weidinger, Matthias Wielscher, Catherine L. Worth, Chen-jian Xu, Young-ae Lee

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Article number6618
JournalNature Communications
Issue number1
Early online date16 Nov 2021
Publication statusPublished - 1 Dec 2021


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