Multiple common variants for celiac disease influencing immune gene expression

Patrick C. A. Dubois, Gosia Trynka, Lude Franke, Karen A. Hunt, Jihane Romanos, Alessandra Curtotti, Alexandra Zhernakova, Graham A. R. Heap, Roza Adany, Arpo Aromaa, Maria Teresa Bardella, Leonard H. van den Berg, Nicholas A. Bockett, Emilio G. de la Concha, Barbara Dema, Rudolf S. N. Fehrmann, Miguel Fernandez-Arquero, Szilvia Fiatal, Elvira Grandone, Peter M. GreenHarry J. M. Groen, Rhian Gwilliam, Roderick H. J. Houwen, Sarah E. Hunt, Katri Kaukinen, Dermot Kelleher, Ilma Korponay-Szabo, Kalle Kurppa, Padraic MacMathuna, Markku Maki, Maria Cristina Mazzilli, Owen T. McCann, M. Luisa Mearin, Charles A. Mein, Muddassar M. Mirza, Vanisha Mistry, Barbara Mora, Katherine I. Morley, Chris J. Mulder, Joseph A. Murray, Concepcion Nunez, Elvira Oosterom, Roel A. Ophoff, Isabel Polanco, Leena Peltonen, Mathieu Platteel, Anna Rybak, Veikko Salomaa, Joachim J. Schweizer, Maria Pia Sperandeo, Greetje J. Tack, Graham Turner, Jan H. Veldink, Wieke H. M. Verbeek, Rinse K. Weersma, Victorien M. Wolters, Elena Urcelay, Bozena Cukrowska, Luigi Greco, Susan L. Neuhausen, Ross McManus, Donatella Barisani, Panos Deloukas, Jeffrey C. Barrett, Paivi Saavalainen, Cisca Wijmenga, David A. van Heel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

640 Citations (Scopus)

Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) <10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) <5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P <0.0028, FDR 5%) with cis gene expression.

Original languageEnglish
Pages (from-to)295-U42
Number of pages10
JournalNature Genetics
Volume42
Issue number4
DOIs
Publication statusPublished - Apr-2010

Keywords

  • GENOME-WIDE ASSOCIATION
  • RHEUMATOID-ARTHRITIS
  • SUSCEPTIBILITY LOCI
  • POSITIVE SELECTION
  • RISK VARIANTS
  • POPULATION
  • ALLELES
  • THYMUS
  • HETERODIMER
  • THYMOCYTES

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