University of Oulu

Grosche, S., Marenholz, I., Esparza-Gordillo, J. et al. Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4. Nat Commun 12, 6618 (2021).

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

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Author: Grosche, Sarah1,2,3; Marenholz, Ingo1,2; Esparza-Gordillo, Jorge1,2,4;
Organizations: 1Max Delbruck Ctr MDC Mol Med, Berlin, Germany.
2Charite Univ Med Ctr, Expt & Clin Res Ctr, Clin Pediat Allergy, Berlin, Germany.
3Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.
4GlaxoSmithKline, Stevenage, Herts, England.
5Univ Edinburgh, Roslin Inst, Edinburgh, Midlothian, Scotland.
6Univ Edinburgh, Western Gen Hosp, Inst Genet & Canc, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.
7Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, Copenhagen, Denmark.
8Steno Diabet Ctr Copenhagen, Gentofte, Denmark.
9Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
10Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden.
11Univ Med Greifswald, Clin & Polyclin Dermatol, Greifswald, Germany.
12Univ Hosp Schleswig Holstein, Dept Dermatol Allergol & Venereol, Kiel, Germany.
13Univ Regensburg, Dept Epidemiol & Prevent Med, Regensburg, Germany.
14Univ Edinburgh, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.
15Ctr Res Environm Epidemiol CREAL, ISGlobal, Barcelona, Spain.
16Univ Manchester, Manchester Acad Hlth Sci Ctr, Sch Biol Sci, Div Infect Immun & Resp Med, Manchester, Lancs, England.
17Manchester Univ NHS Fdn Trust, Manchester, Lancs, England.
18Imperial Coll London, Natl Lung & Heart Inst, London, England.
19Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne Sch Populat & Global Hlth, Melbourne, Vic, Australia.
20Univ Valencia, FISABIO Univ Jaume Univ Valencia Joint Res Unit E, Nursing Sch, CIBERESP, Valencia, Spain.
21Kings Coll London, Dept Twins Res & Genet Epidemiol, London, England.
22QIMR Berghofer Med Res Inst, Genet & Computat Biol, Brisbane, Qld, Australia.
23Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany.
24Helmholtz Ctr Munich, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.
25Univ Penn, Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA.
26Univ Penn, Perelman Sch Med, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA.
27Univ Western Australia, Telethon Kids Inst, Perth, WA, Australia.
28Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Genom, Greifswald, Germany.
29Imperial Coll London, MRC PHE Ctr Environm & Hlth, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
30Univ Oulu, Fac Med, Ctr Life Course Hlth Res, Oulu, Finland.
31Univ Oulu, Bioctr Oulu, Oulu, Finland.
32Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Pediat Pulmonol & Pediat Allergol, Groningen, Netherlands.
33Charite Univ Med Ctr, Dept Pediat Pulmonol Immunol & Intens Care Med, Berlin, Germany.
34Helmholtz Ctr Munich, Inst Genet Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.
35Univ Sydney, Woolcock Inst Med Res, Sydney, NSW, Australia.
36Ludwig Maximilians Univ Munchen, Inst Med Informat Proc Biometry & Epidemiol IBE, Fac Med, Munich, Germany.
37Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Med Biostat Epidemiol & Informat IMBEI, Mainz, Germany.
38Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany.
39Univ Hosp Bonn, Bonn, Germany.
40Univ Bristol, Bristol Med Sch, MRC Integrat Epidemiol Unit, Populat Hlth Sci, Bristol, Avon, England.
41Univ Newcastle, Fac Med & Hlth, Sch Med & Publ Hlth, Newcastle, NSW, Australia.
42Helmholtz Ctr Munich, Inst Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.
43Murdoch Childrens Res Inst, Resp Res, Melbourne, Vic, Australia.
44Usher Inst Populat Hlth Sci & Informat, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland.
45Univ Western Australia, Inst Resp Hlth, Sch Biomed Sci, Nedlands, WA, Australia.
46Univ Western Australia, Ctr Resp Hlth, Sch Biomed Sci, Nedlands, WA, Australia.
47Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, Dept Epidemiol, Groningen, Netherlands.
48Hannover Med Sch, Ctr Individualized Infect Med CIIM, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.7 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2022-04-05


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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 12
Issue: 1
Article number: 6618
DOI: 10.1038/s41467-021-26783-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: Acknowledgments for each of the participating studies are provided in Supplementary Note 1. Open Access funding enabled and organized by Projekt DEAL.
Copyright information: © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit