Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci

*Genizon BioSciences, Inc., St. Laurent, QC, Canada H4T 2C7;
^‡Institute for Clinical Molecular Biology and
^¶Department of General Internal Medicine, Christian-Albrechts-University Kiel, Schittenhelmstrasse 12, 24105 Kiel, Germany;
^§Centre de Recherche du CHUM, Notre-Dame Hospital, Department of Medicine, University of Montreal, Montreal, QC, Canada H2L 4M1;
^‖Therapeutic Gastroenterology, McGill University, Montreal, QC, Canada H3A 1A1; and
**Department of Bioinformatics, Genentech, Inc., South San Francisco, CA 94080

Communicated by Raymond L. White, University of California, San Francisco, Emeryville, CA, July 25, 2007 (received for review April 9, 2007)

Abstract

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.

Footnotes

^†To whom correspondence should be addressed. E-mail: john.raelson{at}genizon.com
Author contributions: J.V.R., R.D.L., A.R., T.P.K., and A.B. contributed equally to this work; J.V.R., P.V.E., R.J.P., J.W.H., T.P.K., A.B., and S.S. designed research; R.D.L., A.R., H.F., B.P., P.V.E., P.C., Q.N.-H., J.S., S.D., R.A., P.R., A.F., G.J., S.N., J.-M.V., P.S., N.L., T.P.K., and A.B. performed research; J.V.R., R.D.L., A.R., H.F., B.P., P.V.E., W.E.C.B., P.C., Q.N.-H., J.S., S.D., R.A., P.R., A.F., G.J., S.N., J.-M.V., P.S., N.L., H.F.C., R.J.P., J.W.H., T.P.K., and A.B. analyzed data; and J.V.R., R.D.L., T.P.K., and S.S. wrote the paper;
Conflict of interest statement: Genizon BioSciences, Inc., has received all commercial rights in the collaboration from the University Hospital Schleswig–Holstein. S.S. is a member of the scientific advisory board of Applied Biosystems, Inc., and has consulted for Abbott, Centocor, and Schering–Plough.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706645104/DC1.
Abbreviations:

GWA,

genome-wide association;

CD,

Crohn's disease;

QFP,

Quebec Founder Population;

FM,

fine mapping;

C.I.,

confidence interval;

OR,

odds ratio;

LD,

linkage disequilibrium.
Freely available online through the PNAS open access option.