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

Grosche, Sarah; Marenholz, Ingo; Bisgaard, Hans; Bønnelykke, Klaus; Brown, Sara J.; Bustamante, Mariona; Curtin, John A.; Custovic, Adnan; Dharmage, Shyamali C.; Esplugues, Ana; Falchi, Mario; Fernandez-Orth, Dietmar; Esparza-Gordillo, Jorge; Ferreira, Manuel A. R.; Franke, A; Gerdes, S; Gieger, C; Hakonarson, H; Holt, PG; Homuth, G; Hubner, N; Hysi, PG; Jarvelin, M-R; Arnau-Soler, Aleix; Karlsson, R; Koppelman, GH; Lau, S; Lutz, M; Magnusson, PKE; Marks, GB; Mueller-Nurasyid, M; Noethen, MM; Paternoster, L; Pennell, Craig E.; Pairo-Castineira, Erola; Peters, A; Rawlik, K; Robertson, CF; Rodriguez, E; Sebert, S; Simpson, A; Sleiman, PMA; Standl, M; Stoelzl, D; Strauch, K; Rüschendorf, Franz; Szwajda, A; Tenesa, A; Thompson, PJ; Ullemar, V; Visconti, A; Vonk, JM; Wang, CA; Weidinger, S; Wielscher, M; Worth, CL; Ahluwalia, Tarunveer S.; Xu, C-J; Lee, Y-A; Almqvist, Catarina; Arnold, Andreas; Baurecht, Hansjörg

Title: Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
Creator: Grosche, Sarah; Marenholz, Ingo; Bisgaard, Hans; Bønnelykke, Klaus; Brown, Sara J.; Bustamante, Mariona; Curtin, John A.; Custovic, Adnan; Dharmage, Shyamali C.; Esplugues, Ana; Falchi, Mario; Fernandez-Orth, Dietmar; Esparza-Gordillo, Jorge; Ferreira, Manuel A. R.; Franke, A; Gerdes, S; Gieger, C; Hakonarson, H; Holt, PG; Homuth, G; Hubner, N; Hysi, PG; Jarvelin, M-R; Arnau-Soler, Aleix; Karlsson, R; Koppelman, GH; Lau, S; Lutz, M; Magnusson, PKE; Marks, GB; Mueller-Nurasyid, M; Noethen, MM; Paternoster, L; Pennell, Craig E.; Pairo-Castineira, Erola; Peters, A; Rawlik, K; Robertson, CF; Rodriguez, E; Sebert, S; Simpson, A; Sleiman, PMA; Standl, M; Stoelzl, D; Strauch, K; Rüschendorf, Franz; Szwajda, A; Tenesa, A; Thompson, PJ; Ullemar, V; Visconti, A; Vonk, JM; Wang, CA; Weidinger, S; Wielscher, M; Worth, CL; Ahluwalia, Tarunveer S.; Xu, C-J; Lee, Y-A; Almqvist, Catarina; Arnold, Andreas; Baurecht, Hansjörg
Relation: Nature Communications Vol. 12, Issue 1, no. 6618
Publisher Link: http://dx.doi.org/10.1038/s41467-021-26783-x
Publisher: Nature Publishing Group
Resource Type: journal article
Date: 2021
Description: 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.
Subject: rare variants; eczema; rare diseases; receptor
Identifier: http://hdl.handle.net/1959.13/1452042
Identifier: uon:44342
Identifier: ISSN:2041-1723
Language: eng
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