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. Ferreira; Andre 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

doi:10.1038/s41467-021-26783-x

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

Division of Immunology, Immunity to Infection and Respiratory Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	6618
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	16 Nov 2021
DOIs	https://doi.org/10.1038/s41467-021-26783-x
Publication status	Published - 1 Dec 2021

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Grosche, S., Marenholz, I., Esparza-gordillo, J., Arnau-soler, A., Pairo-castineira, E., Rüschendorf, F., Ahluwalia, T. S., Almqvist, C., Arnold, A., Baurecht, H., Bisgaard, H., Bønnelykke, K., Brown, S. J., Bustamante, M., Curtin, J. A., Dharmage, S. C., Esplugues, A., Falchi, M., Fernandez-orth, D., ... Lee, Y. (2021). Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4. Nature Communications, 12(1), Article 6618. https://doi.org/10.1038/s41467-021-26783-x

@article{9e507ba9b4434b959266b81bb428aacb,

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

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.",

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

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-26783-x",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Grosche, S, Marenholz, I, Esparza-gordillo, J, Arnau-soler, A, Pairo-castineira, E, Rüschendorf, F, Ahluwalia, TS, Almqvist, C, Arnold, A, Baurecht, H, Bisgaard, H, Bønnelykke, K, Brown, SJ, Bustamante, M, Curtin, JA, Dharmage, SC, Esplugues, A, Falchi, M, Fernandez-orth, D, Ferreira, MAR, Franke, A, Gerdes, S, Gieger, C, Hakonarson, H, Holt, PG, Homuth, G, Hubner, N, Hysi, PG, Jarvelin, M, Karlsson, R, Koppelman, GH, Lau, S, Lutz, M, Magnusson, PKE, Marks, GB, Müller-nurasyid, M, Nöthen, MM, Paternoster, L, Pennell, CE, Peters, A, Rawlik, K, Robertson, CF, Rodriguez, E, Sebert, S, Simpson, A, Sleiman, PMA, Standl, M, Stölzl, D, Strauch, K, Szwajda, A, Tenesa, A, Ullemar, V, Visconti, A, Vonk, JM, Wang, CA, Weidinger, S, Wielscher, M, Worth, CL, Xu, C & Lee, Y 2021, 'Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4', Nature Communications, vol. 12, no. 1, 6618. https://doi.org/10.1038/s41467-021-26783-x

TY - JOUR

T1 - Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4

AU - Grosche, Sarah

AU - Marenholz, Ingo

AU - Esparza-gordillo, Jorge

AU - Arnau-soler, Aleix

AU - Pairo-castineira, Erola

AU - Rüschendorf, Franz

AU - Ahluwalia, Tarunveer S.

AU - Almqvist, Catarina

AU - Arnold, Andreas

AU - Baurecht, Hansjörg

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

AU - Brown, Sara J.

AU - Bustamante, Mariona

AU - Curtin, John A.

AU - Dharmage, Shyamali C.

AU - Esplugues, Ana

AU - Falchi, Mario

AU - Fernandez-orth, Dietmar

AU - Ferreira, Manuel A. R.

AU - Franke, Andre

AU - Gerdes, Sascha

AU - Gieger, Christian

AU - Hakonarson, Hakon

AU - Holt, Patrick G.

AU - Homuth, Georg

AU - Hubner, Norbert

AU - Hysi, Pirro G.

AU - Jarvelin, Marjo-riitta

AU - Karlsson, Robert

AU - Koppelman, Gerard H.

AU - Lau, Susanne

AU - Lutz, Manuel

AU - Magnusson, Patrik K. E.

AU - Marks, Guy B.

AU - Müller-nurasyid, Martina

AU - Nöthen, Markus M.

AU - Paternoster, Lavinia

AU - Pennell, Craig E.

AU - Peters, Annette

AU - Rawlik, Konrad

AU - Robertson, Colin F.

AU - Rodriguez, Elke

AU - Sebert, Sylvain

AU - Simpson, Angela

AU - Sleiman, Patrick M. A.

AU - Standl, Marie

AU - Stölzl, Dora

AU - Strauch, Konstantin

AU - Szwajda, Agnieszka

AU - Tenesa, Albert

AU - Ullemar, Vilhelmina

AU - Visconti, Alessia

AU - Vonk, Judith M.

AU - Wang, Carol A.

AU - Weidinger, Stephan

AU - Wielscher, Matthias

AU - Worth, Catherine L.

AU - Xu, Chen-jian

AU - Lee, Young-ae

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-021-26783-x

DO - 10.1038/s41467-021-26783-x

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6618

ER -

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

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