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Meta-Analysis
. 2018 Jan;50(1):42-53.
doi: 10.1038/s41588-017-0014-7. Epub 2017 Dec 22.

Multiancestry Association Study Identifies New Asthma Risk Loci That Colocalize With Immune-Cell Enhancer Marks

Florence Demenais  1   2 Patricia Margaritte-Jeannin  3   4 Kathleen C Barnes  5 William O C Cookson  6 Janine Altmüller  7 Wei Ang  8 R Graham Barr  9 Terri H Beaty  10 Allan B Becker  11 John Beilby  12 Hans Bisgaard  13 Unnur Steina Bjornsdottir  14 Eugene Bleecker  15 Klaus Bønnelykke  13 Dorret I Boomsma  16 Emmanuelle Bouzigon  3   4 Christopher E Brightling  17 Myriam Brossard  3   4 Guy G Brusselle  18   19   20 Esteban Burchard  21 Kristin M Burkart  22 Andrew Bush  23   24 Moira Chan-Yeung  25 Kian Fan Chung  23   26 Alexessander Couto Alves  27 John A Curtin  28 Adnan Custovic  29 Denise Daley  25   30 Johan C de Jongste  31 Blanca E Del-Rio-Navarro  32 Kathleen M Donohue  9 Liesbeth Duijts  33 Celeste Eng  34 Johan G Eriksson  35 Martin Farrall  36   37 Yuliya Fedorova  38 Bjarke Feenstra  39 Manuel A Ferreira  40 Australian Asthma Genetics Consortium (AAGC) collaboratorsMaxim B Freidin  41 Zofia Gajdos  42   43 Jim Gauderman  44 Ulrike Gehring  45 Frank Geller  39 Jon Genuneit  46 Sina A Gharib  47 Frank Gilliland  44 Raquel Granell  48   49 Penelope E Graves  50 Daniel F Gudbjartsson  51   52 Tari Haahtela  53 Susan R Heckbert  54 Dick Heederik  45 Joachim Heinrich  55   56 Markku Heliövaara  57 John Henderson  48   49 Blanca E Himes  58 Hiroshi Hirose  59 Joel N Hirschhorn  43   60   61 Albert Hofman  19   62 Patrick Holt  63 Jouke Hottenga  16 Thomas J Hudson  64   65 Jennie Hui  12   66   67 Medea Imboden  68   69 Vladimir Ivanov  70 Vincent W V Jaddoe  71 Alan James  72   73 Christer Janson  74 Marjo-Riitta Jarvelin  75   76   77   78 Deborah Jarvis  23   79 Graham Jones  80 Ingileif Jonsdottir  51   81 Pekka Jousilahti  57 Michael Kabesch  82 Mika Kähönen  83 David B Kantor  84   85 Alexandra S Karunas  38   86 Elza Khusnutdinova  38   86 Gerard H Koppelman  87   88 Anita L Kozyrskyj  89 Eskil Kreiner  13 Michiaki Kubo  90 Rajesh Kumar  91   92 Ashish Kumar  68   69   93 Mikko Kuokkanen  57   94 Lies Lahousse  19   95 Tarja Laitinen  96 Catherine Laprise  97   98 Mark Lathrop  99 Susanne Lau  100 Young-Ae Lee  101   102 Terho Lehtimäki  103 Sébastien Letort  3   4 Albert M Levin  104 Guo Li  47 Liming Liang  62   105 Laura R Loehr  106 Stephanie J London  107 Daan W Loth  19 Ani Manichaikul  108 Ingo Marenholz  101   102 Fernando J Martinez  50 Melanie C Matheson  109 Rasika A Mathias  110 Kenji Matsumoto  111 Hamdi Mbarek  16 Wendy L McArdle  112 Mads Melbye  39   113   114 Erik Melén  93   115   116 Deborah Meyers  15 Sven Michel  82 Hamida Mohamdi  3   4 Arthur W Musk  117   118 Rachel A Myers  119 Maartje A E Nieuwenhuis  88   120 Emiko Noguchi  121 George T O'Connor  122   123 Ludmila M Ogorodova  124 Cameron D Palmer  43   60 Aarno Palotie  94   125   126 Julie E Park  25 Craig E Pennell  8 Göran Pershagen  93   115 Alexey Polonikov  70 Dirkje S Postma  88   120 Nicole Probst-Hensch  68   69 Valery P Puzyrev  41 Benjamin A Raby  127 Olli T Raitakari  128 Adaikalavan Ramasamy  27   129 Stephen S Rich  108 Colin F Robertson  130 Isabelle Romieu  131   132 Muhammad T Salam  44   133 Veikko Salomaa  57 Vivi Schlünssen  134 Robert Scott  135 Polina A Selivanova  136 Torben Sigsgaard  134 Angela Simpson  28   137 Valérie Siroux  138   139 Lewis J Smith  140 Maria Solodilova  70 Marie Standl  56 Kari Stefansson  51   81 David P Strachan  141 Bruno H Stricker  19   142   143 Atsushi Takahashi  90 Philip J Thompson  144 Gudmar Thorleifsson  51 Unnur Thorsteinsdottir  51   81 Carla M T Tiesler  56   145 Dara G Torgerson  34 Tatsuhiko Tsunoda  90   146 André G Uitterlinden  143 Ralf J P van der Valk  147 Amaury Vaysse  3   4 Sailaja Vedantam  42   43 Andrea von Berg  148 Erika von Mutius  149   150 Judith M Vonk  88   151 Johannes Waage  13 Nick J Wareham  135 Scott T Weiss  127 Wendy B White  152 Magnus Wickman  93   153 Elisabeth Widén  94 Gonneke Willemsen  16 L Keoki Williams  154   155 Inge M Wouters  45 James J Yang  156 Jing Hua Zhao  135 Miriam F Moffatt  6 Carole Ober  157 Dan L Nicolae  158
Affiliations
Free PMC article
Meta-Analysis

Multiancestry Association Study Identifies New Asthma Risk Loci That Colocalize With Immune-Cell Enhancer Marks

Florence Demenais et al. Nat Genet. .
Free PMC article

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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