Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

Florence Demenais, Patricia Margaritte-Jeannin, Kathleen C Barnes, William O C Cookson, Janine Altmüller, Wei Ang, R Graham Barr, Terri H Beaty, Allan B Becker, John Beilby, Hans Bisgaard, Unnur Steina Bjornsdottir, Eugene Bleecker, Klaus Bønnelykke, Dorret I Boomsma, Emmanuelle Bouzigon, Christopher E Brightling, Myriam Brossard, Guy G Brusselle, Esteban Burchard, Kristin M Burkart, Andrew Bush, Moira Chan-Yeung, Kian Fan Chung, Alexessander Couto Alves, John A Curtin, Adnan Custovic, Denise Daley, Johan C de Jongste, Blanca E Del-Rio-Navarro, Kathleen M Donohue, Liesbeth Duijts, Celeste Eng, Johan G Eriksson, Martin Farrall, Yuliya Fedorova, Bjarke Feenstra, Manuel A Ferreira, Australian Asthma Genetics Consortium (AAGC) collaborators, Maxim B Freidin, Zofia Gajdos, Jim Gauderman, Ulrike Gehring, Frank Geller, Jon Genuneit, Sina A Gharib, Frank Gilliland, Raquel Granell, Penelope E Graves, Daniel F Gudbjartsson, Tari Haahtela, Susan R Heckbert, Dick Heederik, Joachim Heinrich, Markku Heliövaara, John Henderson, Blanca E Himes, Hiroshi Hirose, Joel N Hirschhorn, Albert Hofman, Patrick Holt, Jouke Hottenga, Thomas J Hudson, Jennie Hui, Medea Imboden, Vladimir Ivanov, Vincent W V Jaddoe, Alan James, Christer Janson, Marjo-Riitta Jarvelin, Deborah Jarvis, Graham Jones, Ingileif Jonsdottir, Pekka Jousilahti, Michael Kabesch, Mika Kähönen, David B Kantor, Alexandra S Karunas, Elza Khusnutdinova, Gerard H Koppelman, Anita L Kozyrskyj, Eskil Kreiner, Michiaki Kubo, Rajesh Kumar, Ashish Kumar, Mikko Kuokkanen, Lies Lahousse, Tarja Laitinen, Catherine Laprise, Mark Lathrop, Susanne Lau, Young-Ae Lee, Terho Lehtimäki, Sébastien Letort, Albert M Levin, Guo Li, Liming Liang, Laura R Loehr, Stephanie J London, Daan W Loth, Ani Manichaikul, Ingo Marenholz, Fernando J Martinez, Melanie C Matheson, Rasika A Mathias, Kenji Matsumoto, Hamdi Mbarek, Wendy L McArdle, Mads Melbye, Erik Melén, Deborah Meyers, Sven Michel, Hamida Mohamdi, Arthur W Musk, Rachel A Myers, Maartje A E Nieuwenhuis, Emiko Noguchi, George T O'Connor, Ludmila M Ogorodova, Cameron D Palmer, Aarno Palotie, Julie E Park, Craig E Pennell, Göran Pershagen, Alexey Polonikov, Dirkje S Postma, Nicole Probst-Hensch, Valery P Puzyrev, Benjamin A Raby, Olli T Raitakari, Adaikalavan Ramasamy, Stephen S Rich, Colin F Robertson, Isabelle Romieu, Muhammad T Salam, Veikko Salomaa, Vivi Schlünssen, Robert Scott, Polina A Selivanova, Torben Sigsgaard, Angela Simpson, Valérie Siroux, Lewis J Smith, Maria Solodilova, Marie Standl, Kari Stefansson, David P Strachan, Bruno H Stricker, Atsushi Takahashi, Philip J Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Carla M T Tiesler, Dara G Torgerson, Tatsuhiko Tsunoda, André G Uitterlinden, Ralf J P van der Valk, Amaury Vaysse, Sailaja Vedantam, Andrea von Berg, Erika von Mutius, Judith M Vonk, Johannes Waage, Nick J Wareham, Scott T Weiss, Wendy B White, Magnus Wickman, Elisabeth Widén, Gonneke Willemsen, L Keoki Williams, Inge M Wouters, James J Yang, Jing Hua Zhao, Miriam F Moffatt, Carole Ober, Dan L Nicolae, Florence Demenais, Patricia Margaritte-Jeannin, Kathleen C Barnes, William O C Cookson, Janine Altmüller, Wei Ang, R Graham Barr, Terri H Beaty, Allan B Becker, John Beilby, Hans Bisgaard, Unnur Steina Bjornsdottir, Eugene Bleecker, Klaus Bønnelykke, Dorret I Boomsma, Emmanuelle Bouzigon, Christopher E Brightling, Myriam Brossard, Guy G Brusselle, Esteban Burchard, Kristin M Burkart, Andrew Bush, Moira Chan-Yeung, Kian Fan Chung, Alexessander Couto Alves, John A Curtin, Adnan Custovic, Denise Daley, Johan C de Jongste, Blanca E Del-Rio-Navarro, Kathleen M Donohue, Liesbeth Duijts, Celeste Eng, Johan G Eriksson, Martin Farrall, Yuliya Fedorova, Bjarke Feenstra, Manuel A Ferreira, Australian Asthma Genetics Consortium (AAGC) collaborators, Maxim B Freidin, Zofia Gajdos, Jim Gauderman, Ulrike Gehring, Frank Geller, Jon Genuneit, Sina A Gharib, Frank Gilliland, Raquel Granell, Penelope E Graves, Daniel F Gudbjartsson, Tari Haahtela, Susan R Heckbert, Dick Heederik, Joachim Heinrich, Markku Heliövaara, John Henderson, Blanca E Himes, Hiroshi Hirose, Joel N Hirschhorn, Albert Hofman, Patrick Holt, Jouke Hottenga, Thomas J Hudson, Jennie Hui, Medea Imboden, Vladimir Ivanov, Vincent W V Jaddoe, Alan James, Christer Janson, Marjo-Riitta Jarvelin, Deborah Jarvis, Graham Jones, Ingileif Jonsdottir, Pekka Jousilahti, Michael Kabesch, Mika Kähönen, David B Kantor, Alexandra S Karunas, Elza Khusnutdinova, Gerard H Koppelman, Anita L Kozyrskyj, Eskil Kreiner, Michiaki Kubo, Rajesh Kumar, Ashish Kumar, Mikko Kuokkanen, Lies Lahousse, Tarja Laitinen, Catherine Laprise, Mark Lathrop, Susanne Lau, Young-Ae Lee, Terho Lehtimäki, Sébastien Letort, Albert M Levin, Guo Li, Liming Liang, Laura R Loehr, Stephanie J London, Daan W Loth, Ani Manichaikul, Ingo Marenholz, Fernando J Martinez, Melanie C Matheson, Rasika A Mathias, Kenji Matsumoto, Hamdi Mbarek, Wendy L McArdle, Mads Melbye, Erik Melén, Deborah Meyers, Sven Michel, Hamida Mohamdi, Arthur W Musk, Rachel A Myers, Maartje A E Nieuwenhuis, Emiko Noguchi, George T O'Connor, Ludmila M Ogorodova, Cameron D Palmer, Aarno Palotie, Julie E Park, Craig E Pennell, Göran Pershagen, Alexey Polonikov, Dirkje S Postma, Nicole Probst-Hensch, Valery P Puzyrev, Benjamin A Raby, Olli T Raitakari, Adaikalavan Ramasamy, Stephen S Rich, Colin F Robertson, Isabelle Romieu, Muhammad T Salam, Veikko Salomaa, Vivi Schlünssen, Robert Scott, Polina A Selivanova, Torben Sigsgaard, Angela Simpson, Valérie Siroux, Lewis J Smith, Maria Solodilova, Marie Standl, Kari Stefansson, David P Strachan, Bruno H Stricker, Atsushi Takahashi, Philip J Thompson, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Carla M T Tiesler, Dara G Torgerson, Tatsuhiko Tsunoda, André G Uitterlinden, Ralf J P van der Valk, Amaury Vaysse, Sailaja Vedantam, Andrea von Berg, Erika von Mutius, Judith M Vonk, Johannes Waage, Nick J Wareham, Scott T Weiss, Wendy B White, Magnus Wickman, Elisabeth Widén, Gonneke Willemsen, L Keoki Williams, Inge M Wouters, James J Yang, Jing Hua Zhao, Miriam F Moffatt, Carole Ober, Dan L Nicolae

Abstract

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors who are affiliated with deCODE (D.F.G., I.J., K.S., U.T., G.T.) are employees of deCODE genetics/AMGEN. All other co-authors did not declare any conflict of interest

Figures

Figure 1
Figure 1
Manhattan plots of the results of European-ancestry and multi-ancestry random-effects meta-analyses of asthma risk. (a) The European-ancestry meta-analysis pertains to 19,954 cases and 107,715 controls. (b) The multi-ancestry meta-analysis pertains to 23,948 cases and 118,538 controls. Each locus is annotated by its cytogenetic band location. The × axis represents chromosomal location and the y axis represents −log10 (P value) for tests of association between SNPs and asthma. Black, previously known loci; red, new loci identified in the European-ancestry meta-analysis; blue, additional new loci identified in the multi-ancestry meta-analysis The dashed horizontal line denotes P=5×10−8.
Figure 2
Figure 2
GRAIL circle plot of connectivity between genes at asthma risk loci. The 17 asthma risk loci are along the outer ring (the 10p14 locus was ignored because it corresponds to a gene desert); the internal ring represents the genes at these loci. The width of the lines drawn between genes corresponds to the strength of the literature-based connectivity, with thicker lines representing stronger connections.

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