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Crohn's disease and genetic hitchhiking at IBD5.

ABSTRACT: Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn's disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European CEU HapMap population (P=0.0007) and European Human Genome Diversity Panel populations (P?0.01). To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high-density microarray data in a sample of 1,868 Crohn's disease cases and 5,550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease (odds ratio [OR]: 1.05, P=0.21). In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three genes (OR: 1.24, P=2.6×10(-8)), as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn's disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn's disease patients (P=0.0006) and no significant difference in expression of OCTN1. Collectively, these data indicate that the 503F variant has increased in frequency due to recent positive selection and that disease-causing variants in linkage disequilibrium with 503F have hitchhiked to relatively high frequency, thus forming the IBD5 risk haplotype. Finally, our association results and expression data support IRF1 as a strong candidate for Crohn's disease causation.

SUBMITTER: Huff CD

PROVIDER: S-EPMC3245542 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Crohn's disease and genetic hitchhiking at IBD5.

Huff Chad D CD Witherspoon David J DJ Zhang Yuhua Y Gatenbee Chandler C Denson Lee A LA Kugathasan Subra S Hakonarson Hakon H Whiting April A Davis Chadwick T CT Wu Wilfred W Xing Jinchuan J Watkins W Scott WS Bamshad Michael J MJ Bradfield Jonathan P JP Bulayeva Kazima K Simonson Tatum S TS Jorde Lynn B LB Guthery Stephen L SL

Molecular biology and evolution 20110804 1

Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn's disease susceptibility at IBD5 ...[more]

PMID: 21816865

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Project description:BACKGROUND: Few models of genetic hitchhiking in subdivided populations have been developed and the rarity of empirical examples is even more striking. We here provide evidences of genetic hitchhiking in a subdivided population of the marine mussel Mytilus edulis. In the Bay of Biscay (France), a patch of M. edulis populations happens to be separated from its North Sea conspecifics by a wide region occupied only by the sister species M. galloprovincialis. Although genetic differentiation between the two M. edulis regions is largely non-significant at ten marker loci (average FST~0.007), a strong genetic differentiation is observed at a single locus (FST = 0.25). We validated the outlier status of this locus, and analysed DNA sequence polymorphism in order to identify the nature of the selection responsible for the unusual differentiation. RESULTS: We first showed that introgression of M. galloprovincialis alleles was very weak in both populations and did not significantly affect their differentiation. Secondly, we observed the genetic signature of a selective sweep within both M. edulis populations in the form of a star-shaped clade of alleles. This clade was nearly fixed in the North Sea and was segregating at a moderate frequency in the Bay of Biscay, explaining their genetic differentiation. Incomplete fixation reveals that selection was not direct on the locus but that the studied sequence recombined with a positively selected allele at a linked locus while it was on its way to fixation. Finally, using a deterministic model we showed that the wave of advance of a favourable allele at a linked locus, when crossing a strong enough barrier to gene flow, generates a step in neutral allele frequencies comparable to the step observed between the two M. edulis populations at the outlier locus. In our case, the position of the barrier is now materialised by a large patch of heterospecific M. galloprovincialis populations. CONCLUSION: High FST outlier loci are usually interpreted as being the consequence of ongoing divergent local adaptation. Combining models and data we show that among-population differentiation can also dramatically increase following a selective sweep in a structured population. Our study illustrates how a striking geographical pattern of neutral diversity can emerge from past indirect hitchhiking selection in a structured population. NOTE: Nucleotide sequences reported in this paper are available in the GenBanktrade mark database under the accession numbers EU684165 - EU684228.

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Crohn's disease and genetic hitchhiking at IBD5.

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Crohn's disease and genetic hitchhiking at IBD5.

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