Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.
Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12,014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Ciara
C
Coleman
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Emma M
EM
Quinn
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Anthony W
AW
Ryan
Conway Institute, University College Dublin, Dublin, Ireland.
Judith
J
Conroy
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Valerie
V
Trimble
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Nasir
N
Mahmud
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Nicholas
N
Kennedy
Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
Aiden P
AP
Corvin
CogGene Group, Discipline of Biochemistry and School of Psychology, National University of Ireland Galway, Galway, Ireland.
Derek W
DW
Morris
CogGene Group, Discipline of Biochemistry and School of Psychology, National University of Ireland Galway, Galway, Ireland.
Gary
G
Donohoe
Department of Medicine, Trinity College Dublin, Adelaide and Meath Hospital, Tallagh, Dublin, Ireland.
Colm
C
O'Morain
Department of Gastroenterology, Mater Misercordiae Hospital, Dublin, Ireland.
Padraic
P
MacMathuna
Department of Gastroenterology, University College Hospital, Galway, Ireland.
Valerie
V
Byrnes
Department of Gastroenterology, University College Hospital, Galway, Ireland.
Clifford
C
Kiat
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Gosia
http://orcid.org/0000-0002-6955-9529
G
Trynka
Genetics Department, University Medical Center and University of Groningen, Groningen, The Netherlands.
Cisca
C
Wijmenga
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Dermot
D
Kelleher
Conway Institute, University College Dublin, Dublin, Ireland.
Sean
S
Ennis
Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.
Richard J L
RJ
Anney
Department of Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.
Ross
R
McManus
D000483:Alleles; D004268:DNA-Binding Proteins; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D005903:Gliadin / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007107:Immune System; D007413:Intestinal Mucosa / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D006683:HLA-DQ Antigens; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C466083:ZNF335 protein, human; D005903:Gliadin