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1. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, Paternoster, Lavinia, Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, and Paternoster, Lavinia

Abstract

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023

2. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, Paternoster, Lavinia, Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, and Paternoster, Lavinia

Abstract

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023

3. Quantitative proteomics identifies reduced NRF2 activity and mitochondrial dysfunction in Atopic Dermatitis

Author

Koch, Michael, Kockmann, Tobias, Rodriguez, Elke, Wehkamp, Ulrike, Hiebert, Paul, Ben-Yehuda Greenwald, Maya, Stölzl, Dora, Beer, Hans-Dietmar, Tschachler, Erwin, Weidinger, Stephan, Werner, Sabine, auf dem Keller, Ulrich, Koch, Michael, Kockmann, Tobias, Rodriguez, Elke, Wehkamp, Ulrike, Hiebert, Paul, Ben-Yehuda Greenwald, Maya, Stölzl, Dora, Beer, Hans-Dietmar, Tschachler, Erwin, Weidinger, Stephan, Werner, Sabine, and auf dem Keller, Ulrich

Abstract

Atopic Dermatitis (AD) is the most common inflammatory skin disease and characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in AD pathogenesis, but the alterations in the proteome that occur in the full epidermis have not been defined. Using a pressure-cycling technology and data-independent acquisition approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and non-lesional patient skin. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry and immunofluorescence staining. Proteins that were differentially abundant in the epidermis of AD vs. control patients reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification that already characterizes non-lesional skin. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the affected epidermis. Analysis of primary human keratinocytes with siRNA-mediated NRF2 knock-down revealed that the impaired NRF2 activation and mitochondrial abnormalities are partially interlinked. These results provide insight into the molecular alterations in the epidermis of AD patients and identify potential targets for pharmaceutical intervention.

Published
2023

4. Quantitative proteomics identifies reduced NRF2 activity and mitochondrial dysfunction in Atopic Dermatitis

Author

Koch, Michael, Kockmann, Tobias, Rodriguez, Elke, Wehkamp, Ulrike, Hiebert, Paul, Ben-Yehuda Greenwald, Maya, Stölzl, Dora, Beer, Hans-Dietmar, Tschachler, Erwin, Weidinger, Stephan, Werner, Sabine, auf dem Keller, Ulrich, Koch, Michael, Kockmann, Tobias, Rodriguez, Elke, Wehkamp, Ulrike, Hiebert, Paul, Ben-Yehuda Greenwald, Maya, Stölzl, Dora, Beer, Hans-Dietmar, Tschachler, Erwin, Weidinger, Stephan, Werner, Sabine, and auf dem Keller, Ulrich

Abstract

Atopic Dermatitis (AD) is the most common inflammatory skin disease and characterized by a deficient epidermal barrier and cutaneous inflammation. Genetic studies suggest a key role of keratinocytes in AD pathogenesis, but the alterations in the proteome that occur in the full epidermis have not been defined. Using a pressure-cycling technology and data-independent acquisition approach, we performed quantitative proteomics of epidermis from healthy volunteers and lesional and non-lesional patient skin. Results were validated by targeted proteomics using parallel reaction monitoring mass spectrometry and immunofluorescence staining. Proteins that were differentially abundant in the epidermis of AD vs. control patients reflect the strong inflammation in lesional skin and the defect in keratinocyte differentiation and epidermal stratification that already characterizes non-lesional skin. Most importantly, they reveal impaired activation of the NRF2-antioxidant pathway and reduced abundance of mitochondrial proteins involved in key metabolic pathways in the affected epidermis. Analysis of primary human keratinocytes with siRNA-mediated NRF2 knock-down revealed that the impaired NRF2 activation and mitochondrial abnormalities are partially interlinked. These results provide insight into the molecular alterations in the epidermis of AD patients and identify potential targets for pharmaceutical intervention.

Published
2023

5. European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Author

Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, Paternoster, Lavinia, Budu-Aggrey, Ashley, Kilanowski, Anna, Sobczyk, Maria K., Shringarpure, Suyash S., Mitchell, Ruth, Reis, Kadri, Reigo, Anu, Mägi, Reedik, Nelis, Mari, Tanaka, Nao, Brumpton, Ben M., Thomas, Laurent F., Sole-Navais, Pol, Flatley, Christopher, Espuela-Ortiz, Antonio, Herrera-Luis, Esther, Lominchar, Jesus V.T., Bork-Jensen, Jette, Marenholz, Ingo, Arnau-Soler, Aleix, Jeong, Ayoung, Fawcett, Katherine A., Baurecht, Hansjorg, Rodriguez, Elke, Alves, Alexessander Couto, Kumar, Ashish, Sleiman, Patrick M., Chang, Xiao, Medina-Gomez, Carolina, Hu, Chen, Xu, Cheng jian, Qi, Cancan, El-Heis, Sarah, Titcombe, Philip, Antoun, Elie, Fadista, João, Wang, Carol A., Thiering, Elisabeth, Wu, Baojun, Kress, Sara, Kothalawala, Dilini M., Kadalayil, Latha, Duan, Jiasong, Zhang, Hongmei, Hadebe, Sabelo, Hoffmann, Thomas, Jorgenson, Eric, Choquet, Hélène, Risch, Neil, Njølstad, Pål, Andreassen, Ole A., Johansson, Stefan, Almqvist, Catarina, Gong, Tong, Ullemar, Vilhelmina, Karlsson, Robert, Magnusson, Patrik K.E., Szwajda, Agnieszka, Burchard, Esteban G., Thyssen, Jacob P., Hansen, Torben, Kårhus, Line L., Dantoft, Thomas M., Jeanrenaud, Alexander C.S.N., Ghauri, Ahla, Arnold, Andreas, Homuth, Georg, Lau, Susanne, Nöthen, Markus M., Hübner, Norbert, Imboden, Medea, Visconti, Alessia, Falchi, Mario, Bataille, Veronique, Hysi, Pirro, Ballardini, Natalia, Boomsma, Dorret I., Hottenga, Jouke J., Müller-Nurasyid, Martina, Ahluwalia, Tarunveer S., Stokholm, Jakob, Chawes, Bo, Schoos, Ann Marie M., Esplugues, Ana, Bustamante, Mariona, Raby, Benjamin, Arshad, Syed, German, Chris, Esko, Tõnu, Milani, Lili A., Metspalu, Andres, Terao, Chikashi, Abuabara, Katrina, Løset, Mari, Hveem, Kristian, Jacobsson, Bo, Pino-Yanes, Maria, Strachan, David P., Grarup, Niels, Linneberg, Allan, Lee, Young Ae, Probst-Hensch, Nicole, Weidinger, Stephan, Jarvelin, Marjo Riitta, Melén, Erik, Hakonarson, Hakon, Irvine, Alan D., Jarvis, Deborah, Nijsten, Tamar, Duijts, Liesbeth, Vonk, Judith M., Koppelmann, Gerard H., Godfrey, Keith M., Barton, Sheila J., Feenstra, Bjarke, Pennell, Craig E., Sly, Peter D., Holt, Patrick G., Williams, L. Keoki, Bisgaard, Hans, Bønnelykke, Klaus, Curtin, John, Simpson, Angela, Murray, Clare, Schikowski, Tamara, Bunyavanich, Supinda, Weiss, Scott T., Holloway, John W., Min, Josine L., Brown, Sara J., Standl, Marie, and Paternoster, Lavinia

Abstract

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Published
2023

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

Author

Grosche, Sarah, Marenholz, Ingo, Esparza-Gordillo, Jorge, Arnau-Soler, Aleix, Pairo-Castineira, Erola, Rüschendorf, Franz, Ahluwalia, Tarunveer S., Almqvist, Catarina, Arnold, Andreas, Baurecht, Hansjörg, Bisgaard, Hans, Bønnelykke, Klaus, Brown, Sara J., Bustamante, Mariona, Curtin, John A., Custovic, Adnan, Dharmage, Shyamali C., Esplugues, Ana, Falchi, Mario, Fernandez-Orth, Dietmar, Ferreira, Manuel A.R., Franke, Andre, Gerdes, Sascha, Gieger, Christian, Hakonarson, Hakon, Holt, Patrick G., Homuth, Georg, Hubner, Norbert, Hysi, Pirro G., Jarvelin, Marjo Riitta, Karlsson, Robert, Koppelman, Gerard H., Lau, Susanne, Lutz, Manuel, Magnusson, Patrik K.E., Marks, Guy B., Müller-Nurasyid, Martina, Nöthen, Markus M., Paternoster, Lavinia, Pennell, Craig E., Peters, Annette, Rawlik, Konrad, Robertson, Colin F., Rodriguez, Elke, Sebert, Sylvain, Simpson, Angela, Sleiman, Patrick M.A., Standl, Marie, Stölzl, Dora, Strauch, Konstantin, Grosche, Sarah, Marenholz, Ingo, Esparza-Gordillo, Jorge, Arnau-Soler, Aleix, Pairo-Castineira, Erola, Rüschendorf, Franz, Ahluwalia, Tarunveer S., Almqvist, Catarina, Arnold, Andreas, Baurecht, Hansjörg, Bisgaard, Hans, Bønnelykke, Klaus, Brown, Sara J., Bustamante, Mariona, Curtin, John A., Custovic, Adnan, Dharmage, Shyamali C., Esplugues, Ana, Falchi, Mario, Fernandez-Orth, Dietmar, Ferreira, Manuel A.R., Franke, Andre, Gerdes, Sascha, Gieger, Christian, Hakonarson, Hakon, Holt, Patrick G., Homuth, Georg, Hubner, Norbert, Hysi, Pirro G., Jarvelin, Marjo Riitta, Karlsson, Robert, Koppelman, Gerard H., Lau, Susanne, Lutz, Manuel, Magnusson, Patrik K.E., Marks, Guy B., Müller-Nurasyid, Martina, Nöthen, Markus M., Paternoster, Lavinia, Pennell, Craig E., Peters, Annette, Rawlik, Konrad, Robertson, Colin F., Rodriguez, Elke, Sebert, Sylvain, Simpson, Angela, Sleiman, Patrick M.A., Standl, Marie, Stölzl, Dora, and Strauch, Konstantin

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.

Published
2021

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

Author

Grosche, Sarah, Marenholz, Ingo, Esparza-Gordillo, Jorge, Arnau-Soler, Aleix, Pairo-Castineira, Erola, Rüschendorf, Franz, Ahluwalia, Tarunveer S., Almqvist, Catarina, Arnold, Andreas, Baurecht, Hansjörg, Bisgaard, Hans, Bønnelykke, Klaus, Brown, Sara J., Bustamante, Mariona, Curtin, John A., Custovic, Adnan, Dharmage, Shyamali C., Esplugues, Ana, Falchi, Mario, Fernandez-Orth, Dietmar, Ferreira, Manuel A.R., Franke, Andre, Gerdes, Sascha, Gieger, Christian, Hakonarson, Hakon, Holt, Patrick G., Homuth, Georg, Hubner, Norbert, Hysi, Pirro G., Jarvelin, Marjo Riitta, Karlsson, Robert, Koppelman, Gerard H., Lau, Susanne, Lutz, Manuel, Magnusson, Patrik K.E., Marks, Guy B., Müller-Nurasyid, Martina, Nöthen, Markus M., Paternoster, Lavinia, Pennell, Craig E., Peters, Annette, Rawlik, Konrad, Robertson, Colin F., Rodriguez, Elke, Sebert, Sylvain, Simpson, Angela, Sleiman, Patrick M.A., Standl, Marie, Stölzl, Dora, Strauch, Konstantin, Grosche, Sarah, Marenholz, Ingo, Esparza-Gordillo, Jorge, Arnau-Soler, Aleix, Pairo-Castineira, Erola, Rüschendorf, Franz, Ahluwalia, Tarunveer S., Almqvist, Catarina, Arnold, Andreas, Baurecht, Hansjörg, Bisgaard, Hans, Bønnelykke, Klaus, Brown, Sara J., Bustamante, Mariona, Curtin, John A., Custovic, Adnan, Dharmage, Shyamali C., Esplugues, Ana, Falchi, Mario, Fernandez-Orth, Dietmar, Ferreira, Manuel A.R., Franke, Andre, Gerdes, Sascha, Gieger, Christian, Hakonarson, Hakon, Holt, Patrick G., Homuth, Georg, Hubner, Norbert, Hysi, Pirro G., Jarvelin, Marjo Riitta, Karlsson, Robert, Koppelman, Gerard H., Lau, Susanne, Lutz, Manuel, Magnusson, Patrik K.E., Marks, Guy B., Müller-Nurasyid, Martina, Nöthen, Markus M., Paternoster, Lavinia, Pennell, Craig E., Peters, Annette, Rawlik, Konrad, Robertson, Colin F., Rodriguez, Elke, Sebert, Sylvain, Simpson, Angela, Sleiman, Patrick M.A., Standl, Marie, Stölzl, Dora, and Strauch, Konstantin

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.

Published
2021

8. The power and potential of BIOMAP to elucidate host-microbiome interplay in skin inflammatory diseases

Author

Alenius, Harri, Sinkko, Hanna, Moitinho-Silva, Lucas, Rodriguez, Elke, Broderick, Conor, Alexander, Helen, Reiger, Matthias, Hjelmsø, Mathis Hjort, Fyhrquist, Nanna, Olah, Peter, Bryce, Paul, Smith, Catherine, Koning, Frits, Eyerich, Kilian, Greco, Dario, van den Bogaard, Ellen H., Neumann, Avidan U., Traidl-Hoffmann, Claudia, Homey, Bernhard, Flohr, Carsten, Bønnelykke, Klaus, Stokholm, Jakob, Weidinger, Stephan, Alenius, Harri, Sinkko, Hanna, Moitinho-Silva, Lucas, Rodriguez, Elke, Broderick, Conor, Alexander, Helen, Reiger, Matthias, Hjelmsø, Mathis Hjort, Fyhrquist, Nanna, Olah, Peter, Bryce, Paul, Smith, Catherine, Koning, Frits, Eyerich, Kilian, Greco, Dario, van den Bogaard, Ellen H., Neumann, Avidan U., Traidl-Hoffmann, Claudia, Homey, Bernhard, Flohr, Carsten, Bønnelykke, Klaus, Stokholm, Jakob, and Weidinger, Stephan

Abstract

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis.

Published
2021

9. The power and potential of BIOMAP to elucidate host-microbiome interplay in skin inflammatory diseases

Author

Alenius, Harri, Sinkko, Hanna, Moitinho-Silva, Lucas, Rodriguez, Elke, Broderick, Conor, Alexander, Helen, Reiger, Matthias, Hjelmsø, Mathis Hjort, Fyhrquist, Nanna, Olah, Peter, Bryce, Paul, Smith, Catherine, Koning, Frits, Eyerich, Kilian, Greco, Dario, van den Bogaard, Ellen H., Neumann, Avidan U., Traidl-Hoffmann, Claudia, Homey, Bernhard, Flohr, Carsten, Bønnelykke, Klaus, Stokholm, Jakob, Weidinger, Stephan, Alenius, Harri, Sinkko, Hanna, Moitinho-Silva, Lucas, Rodriguez, Elke, Broderick, Conor, Alexander, Helen, Reiger, Matthias, Hjelmsø, Mathis Hjort, Fyhrquist, Nanna, Olah, Peter, Bryce, Paul, Smith, Catherine, Koning, Frits, Eyerich, Kilian, Greco, Dario, van den Bogaard, Ellen H., Neumann, Avidan U., Traidl-Hoffmann, Claudia, Homey, Bernhard, Flohr, Carsten, Bønnelykke, Klaus, Stokholm, Jakob, and Weidinger, Stephan

Abstract

The two most common chronic inflammatory skin diseases are atopic dermatitis (AD) and psoriasis. The underpinnings of the remarkable degree of clinical heterogeneity of AD and psoriasis are poorly understood and, as a consequence, disease onset and progression are unpredictable and the optimal type and time point for intervention are as yet unknown. The BIOMAP project is the first IMI (Innovative Medicines Initiative) project dedicated to investigating the causes and mechanisms of AD and psoriasis and to identify potential biomarkers responsible for the variation in disease outcome. The consortium includes 7 large pharmaceutical companies and 25 non-industry partners including academia. Since there is mounting evidence supporting an important role for microbial exposures and our microbiota as factors mediating immune polarization and AD and psoriasis pathogenesis, an entire work package is dedicated to the investigation of skin and gut microbiome linked to AD or psoriasis. The large collaborative BIOMAP project will enable the integration of patient cohorts, data and knowledge in unprecedented proportions. The project has a unique opportunity with a potential to bridge and fill the gaps between current problems and solutions. This review highlights the power and potential of the BIOMAP project in the investigation of microbe-host interplay in AD and psoriasis.

Published
2021

10. Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses.

Author

Tsoi, Lam C, Tsoi, Lam C, Rodriguez, Elke, Stölzl, Dora, Wehkamp, Ulrike, Sun, Jingru, Gerdes, Sascha, Sarkar, Mrinal K, Hübenthal, Matthias, Zeng, Chang, Uppala, Ranjitha, Xing, Xianying, Thielking, Frederieke, Billi, Allison C, Swindell, William R, Shefler, Alanna, Chen, Jiahan, Patrick, Matthew T, Harms, Paul W, Kahlenberg, J Michelle, Perez White, Bethany E, Maverakis, Emanual, Gudjonsson, Johann E, Weidinger, Stephan, Tsoi, Lam C, Tsoi, Lam C, Rodriguez, Elke, Stölzl, Dora, Wehkamp, Ulrike, Sun, Jingru, Gerdes, Sascha, Sarkar, Mrinal K, Hübenthal, Matthias, Zeng, Chang, Uppala, Ranjitha, Xing, Xianying, Thielking, Frederieke, Billi, Allison C, Swindell, William R, Shefler, Alanna, Chen, Jiahan, Patrick, Matthew T, Harms, Paul W, Kahlenberg, J Michelle, Perez White, Bethany E, Maverakis, Emanual, Gudjonsson, Johann E, and Weidinger, Stephan

Abstract

BackgroundAlthough multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity.ObjectivesWe sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD.MethodsWe analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings.ResultsOur data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator.ConclusionsOur results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

Published
2020

11. 46th annual congress of the Arbeitsgemeinschaft Dermatologische Forschung in Munich, Germany

Author

Gaffal, Evelyn, Eming, Ruediger, Fabri, Mario, Gebhardt, Christoffer, Stary, Georg, Eyerich, Stefanie, Hoelzel, Michael, Kosnopfel, Corinna, Neubert, Elsa, Rauer, Denise, Rodriguez, Elke, Thiem, Alexander, von Meyenn, Leonhard, Buhl, Timo, Gaffal, Evelyn, Eming, Ruediger, Fabri, Mario, Gebhardt, Christoffer, Stary, Georg, Eyerich, Stefanie, Hoelzel, Michael, Kosnopfel, Corinna, Neubert, Elsa, Rauer, Denise, Rodriguez, Elke, Thiem, Alexander, von Meyenn, Leonhard, and Buhl, Timo

Published
2019

12. Atopic Dermatitis Is an IL-13-Dominant Disease with Greater Molecular Heterogeneity Compared to Psoriasis.

Author

Tsoi, Lam C, Tsoi, Lam C, Rodriguez, Elke, Degenhardt, Frauke, Baurecht, Hansjörg, Wehkamp, Ulrike, Volks, Natalie, Szymczak, Silke, Swindell, William R, Sarkar, Mrinal K, Raja, Kalpana, Shao, Shuai, Patrick, Matthew, Gao, Yilin, Uppala, Ranjitha, Perez White, Bethany E, Getsios, Spiro, Harms, Paul W, Maverakis, Emanual, Elder, James T, Franke, Andre, Gudjonsson, Johann E, Weidinger, Stephan, Tsoi, Lam C, Tsoi, Lam C, Rodriguez, Elke, Degenhardt, Frauke, Baurecht, Hansjörg, Wehkamp, Ulrike, Volks, Natalie, Szymczak, Silke, Swindell, William R, Sarkar, Mrinal K, Raja, Kalpana, Shao, Shuai, Patrick, Matthew, Gao, Yilin, Uppala, Ranjitha, Perez White, Bethany E, Getsios, Spiro, Harms, Paul W, Maverakis, Emanual, Elder, James T, Franke, Andre, Gudjonsson, Johann E, and Weidinger, Stephan

Abstract

Atopic dermatitis (AD) affects up to 20% of children and adults worldwide. To gain a deeper understanding of the pathophysiology of AD, we conducted a large-scale transcriptomic study of AD with deeply sequenced RNA-sequencing samples using long (126-bp) paired-end reads. In addition to the comparisons against previous transcriptomic studies, we conducted in-depth analysis to obtain a high-resolution view of the global architecture of the AD transcriptome and contrasted it with that of psoriasis from the same cohort. By using 147 RNA samples in total, we found striking correlation between dysregulated genes in lesional psoriasis and lesional AD skin with 81% of AD dysregulated genes being shared with psoriasis. However, we described disease-specific molecular and cellular features, with AD skin showing dominance of IL-13 pathways, but with near undetectable IL-4 expression. We also demonstrated greater disease heterogeneity and larger proportion of dysregulated long noncoding RNAs in AD, and illustrated the translational impact, including skin-type classification and drug-target prediction. This study is by far the largest study comparing the AD and psoriasis transcriptomes using RNA sequencing and demonstrating the shared inflammatory components, as well as specific discordant cytokine signatures of these two skin diseases.

Published
2019

13. 46th annual congress of the Arbeitsgemeinschaft Dermatologische Forschung in Munich, Germany

Author

Gaffal, Evelyn, Eming, Ruediger, Fabri, Mario, Gebhardt, Christoffer, Stary, Georg, Eyerich, Stefanie, Hoelzel, Michael, Kosnopfel, Corinna, Neubert, Elsa, Rauer, Denise, Rodriguez, Elke, Thiem, Alexander, von Meyenn, Leonhard, Buhl, Timo, Gaffal, Evelyn, Eming, Ruediger, Fabri, Mario, Gebhardt, Christoffer, Stary, Georg, Eyerich, Stefanie, Hoelzel, Michael, Kosnopfel, Corinna, Neubert, Elsa, Rauer, Denise, Rodriguez, Elke, Thiem, Alexander, von Meyenn, Leonhard, and Buhl, Timo

Published
2019

14. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Author

Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., Barker, Jonathan N., Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., and Barker, Jonathan N.

Abstract

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Published
2017
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15. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Author

Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., Barker, Jonathan N., Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., and Barker, Jonathan N.

Abstract

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Published
2017
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16. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Author

Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., Barker, Jonathan N., Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., and Barker, Jonathan N.

Abstract

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Published
2017
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17. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Author

Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., Barker, Jonathan N., Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., and Barker, Jonathan N.

Abstract

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Published
2017
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18. Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling

Author

Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., Barker, Jonathan N., Dand, Nick, Mucha, Soeren, Tsoi, Lam C., Mahil, Satveer K., Stuart, Philip E., Arnold, Andreas, Baurecht, Hansjoerg, David Burden, A., Callis Duffin, Kristina, Chandran, Vinod, Curtis, Charles J., Das, Sayantan, Ellinghaus, David, Ellinghaus, Eva, Enerbäck, Charlotta, Esko, Tonu, Gladman, Dafna D., Griffiths, Christopher E. M., Gudjonsson, Johann E., Hoffman, Per, Homuth, Georg, Hueffmeier, Ulrike, Krueger, Gerald G., Laudes, Matthias, Hyuck Lee, Sang, Lieb, Wolfgang, Lim, Henry W., Loehr, Sabine, Mrowietz, Ulrich, Mueller-Nurayid, Martina, Noethen, Markus, Peters, Annette, Rahman, Proton, Reis, Andre, Reynolds, Nick J., Rodriguez, Elke, Schmidt, Carsten O., Spain, Sarah L., Strauch, Konstantin, Tejasvi, Trilokraj, Voorhees, John J., Warren, Richard B., Weichenthal, Michael, Weidinger, Stephan, Zawistowski, Matthew, Nair, Rajan P., Capon, Francesca, Smith, Catherine H., Trembath, Richard C., Abecasis, Goncalo R., Elder, James T., Franke, Andre, Simpson, Michael A., and Barker, Jonathan N.

Abstract

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 x 10(-8), OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency amp;lt; 0.01) via gene-wide aggregation testing (IFIH1: p(burden) = 2.53 x 10(-7), OR = 0.707; TYK2: p(burden) = 6.17 x 10(-4), OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted., Funding Agencies|Medical Research Council (MRC) Stratified Medicine award [MR/L011808/1]; Psoriasis Association [RG2/10]; MRC Clinical Training Fellowship [MR/L001543/1]; NIHR Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust; Kings College London; NIHR Biomedical Research Centre at South London; Maudsley NHS Foundation Trust; Maudsley Charity [980]; Guys and St Thomass Charity [STR130505]; MRC grant [G0000934]; Wellcome Trust grant [068545/Z/02]; German Federal Ministry of Education and Research (BMBF) [01ZX1306A]; PopGen Biobank (Kiel, Germany) [01EY1103]; Helmholtz Zentrum Munchen - German Research Center for Environmental Health; BMBF; State of Bavaria; Munich Center of Health Sciences (MC Health); Ludwig-Maximilians-Universitat, of LMUinnovativ; BMBF [01ZZ9603, 01ZZ0103, 01ZZ0403, 03152061A, 03Z1CN22]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg -West Pomerania; network Greifswald Approach to Individualized Medicine (GANI MED); Federal State of Mecklenburg West Pomerania; BMBF Metarthros grant [01EC1407A]; National Institutes of Health [R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183]; GAIN award from the Foundation for the National Institutes of Health; Ann Arbor Veterans Affairs Hospital; Taubman Medical Research Institute; International Psoriasis Council

Published
2017
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19. Meta-analysis identifies seven susceptibility loci involved in the atopic march

Author

Marenholz, Ingo, Esparza-Gordillo, Jorge, Rueschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjoerg, Margaritte-Jeannin, Patricia, Saaf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Soderhall, Cilla, Pershagen, Goran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrlaender, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Foelster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Noethen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Huebner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melen, Erik, Dizier, Marie-Helene, Henderson, A. John, Lee, Young Ae, Marenholz, Ingo, Esparza-Gordillo, Jorge, Rueschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjoerg, Margaritte-Jeannin, Patricia, Saaf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Soderhall, Cilla, Pershagen, Goran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrlaender, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Foelster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Noethen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Huebner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melen, Erik, Dizier, Marie-Helene, Henderson, A. John, and Lee, Young Ae

Abstract

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Published
2015

20. Meta-analysis identifies seven susceptibility loci involved in the atopic march

Author

Marenholz, Ingo, Esparza-Gordillo, Jorge, Rueschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjoerg, Margaritte-Jeannin, Patricia, Saaf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Soderhall, Cilla, Pershagen, Goran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrlaender, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Foelster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Noethen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Huebner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melen, Erik, Dizier, Marie-Helene, Henderson, A. John, Lee, Young Ae, Marenholz, Ingo, Esparza-Gordillo, Jorge, Rueschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjoerg, Margaritte-Jeannin, Patricia, Saaf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Soderhall, Cilla, Pershagen, Goran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrlaender, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Foelster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Noethen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Huebner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melen, Erik, Dizier, Marie-Helene, Henderson, A. John, and Lee, Young Ae

Abstract

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P = 2.1 x 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P = 5.3 x 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Published
2015

21. Meta-analysis identifies seven susceptibility loci involved in the atopic march

Author

Marenholz, Ingo, Esparza-Gordillo, Jorge, Rüschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjörg, Margaritte-Jeannin, Patricia, Sääf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Söderhäll, Cilla, Pershagen, Göran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrländer, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Fölster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Nöthen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Hübner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melén, Erik, Dizier, Marie- Hélène, Henderson, A John, Lee, Young Ae, Marenholz, Ingo, Esparza-Gordillo, Jorge, Rüschendorf, Franz, Bauerfeind, Anja, Strachan, David P., Spycher, Ben D., Baurecht, Hansjörg, Margaritte-Jeannin, Patricia, Sääf, Annika, Kerkhof, Marjan, Ege, Markus, Baltic, Svetlana, Matheson, Melanie C., Li, Jin, Michel, Sven, Ang, Wei Q., McArdle, Wendy, Arnold, Andreas, Homuth, Georg, Demenais, Florence, Bouzigon, Emmanuelle, Söderhäll, Cilla, Pershagen, Göran, de Jongste, Johan C., Postma, Dirkje S., Braun-Fahrländer, Charlotte, Horak, Elisabeth, Ogorodova, Ludmila M., Puzyrev, Valery P., Bragina, Elena Yu, Hudson, Thomas J., Morin, Charles, Duffy, David L., Marks, Guy B., Robertson, Colin F., Montgomery, Grant W., Musk, Bill, Thompson, Philip J., Martin, Nicholas G., James, Alan, Sleiman, Patrick, Toskala, Elina, Rodriguez, Elke, Fölster-Holst, Regina, Franke, Andre, Lieb, Wolfgang, Gieger, Christian, Heinzmann, Andrea, Rietschel, Ernst, Keil, Thomas, Cichon, Sven, Nöthen, Markus M., Pennell, Craig E., Sly, Peter D., Schmidt, Carsten O., Matanovic, Anja, Schneider, Valentin, Heinig, Matthias, Hübner, Norbert, Holt, Patrick G., Lau, Susanne, Kabesch, Michael, Weidinger, Stefan, Hakonarson, Hakon, Ferreira, Manuel A. R., Laprise, Catherine, Freidin, Maxim B., Genuneit, Jon, Koppelman, Gerard H., Melén, Erik, Dizier, Marie- Hélène, Henderson, A John, and Lee, Young Ae

Abstract

Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Published
2015
Full Text
View/download PDF

22. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus

Author

Weidinger, Stephan, Gieger, Christian, Rodriguez, Elke, Baurecht, Hansjörg, Mempel, Martin, Klopp, Norman, Gohlke, Henning, Wagenpfeil, Stefan, Ollert, Markus, Ring, Johannes, Behrendt, Heidrun, Heinrich, Joachim, Novak, Natalija, Bieber, Thomas, Krämer, Ursula, Berdel, Dietrich, Von Berg, Andrea, Bauer, Carl Peter, Herbarth, Olf, Koletzko, Sibylle, Prokisch, Holger, Mehta, Divya, Meitinger, Thomas, Depner, Martin, Von Mutius, Erika, Liang, Liming, Moffatt, Miriam, Cookson, William, Kabesch, Michael, Wichmann, H. Erich, Illig, Thomas, Weidinger, Stephan, Gieger, Christian, Rodriguez, Elke, Baurecht, Hansjörg, Mempel, Martin, Klopp, Norman, Gohlke, Henning, Wagenpfeil, Stefan, Ollert, Markus, Ring, Johannes, Behrendt, Heidrun, Heinrich, Joachim, Novak, Natalija, Bieber, Thomas, Krämer, Ursula, Berdel, Dietrich, Von Berg, Andrea, Bauer, Carl Peter, Herbarth, Olf, Koletzko, Sibylle, Prokisch, Holger, Mehta, Divya, Meitinger, Thomas, Depner, Martin, Von Mutius, Erika, Liang, Liming, Moffatt, Miriam, Cookson, William, Kabesch, Michael, Wichmann, H. Erich, and Illig, Thomas

Abstract

High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85 × 10-20 and 7.08 × 10-19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78 × 10-4 and P = 1.95 × 10-3). The "top" SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28 × 10 -7-4.46 × 10-8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.

Published
2008

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