Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.

Nat Genet 2011 Nov 6;43(12):1193-201. Epub 2011 Nov 6.

Genetics Department, University Medical Center and University of Groningen, The Netherlands.

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242065PMC
November 2011
112 Reads
1 Citation
29.350 Impact Factor

Publication Analysis

Top Keywords

celiac disease
16
signals celiac
8
risk loci
8
association signals
8
dense genotyping
8
disease
5
signals
5
number loci
4
loci including
4
bringing number
4
significance bringing
4
instances gene
4
genes instances
4
including hla
4
signals one-third
4
one-third loci
4
single genes
4
independent association
4
locus multiple
4
multiple independent
4

References

(Supplied by CrossRef)
Article in Br. Med. J.
PJ Bingley et al.
Br. Med. J. 2004
Article in Gut
J West et al.
Gut 2003
Article in Nat. Genet.
DA van Heel et al.
Nat. Genet. 2007
Article in Nat. Genet.
KA Hunt et al.
Nat. Genet. 2008
Article in Nat. Genet.
PC Dubois et al.
Nat. Genet. 2010
Article in Gut
G Trynka et al.
Gut 2009
Article in Nat. Rev. Genet.
A Zhernakova et al.
Nat. Rev. Genet. 2009
Article in N. Engl. J. Med.
DJ Smyth et al.
N. Engl. J. Med. 2008
Article in PLoS Genet.
A Zhernakova et al.
PLoS Genet. 2011
Article in Arthritis Res. Ther.
A Cortes et al.
Arthritis Res. Ther. 2011

Similar Publications