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Improved risk prediction for Crohn's disease with a multi-locus approach.

ABSTRACT: Genome-wide association studies have identified numerous loci demonstrating genome-wide significant association with Crohn's disease. However, when many single nucleotide polymorphisms (SNPs) have weak-to-moderate disease risks, genetic risk prediction models based only on those markers that pass the most stringent statistical significance testing threshold may be suboptimal. Haplotype-based predictive models may provide advantages over single-SNP approaches by facilitating detection of associations driven by cis-interactions among nearby SNPs. In addition, these approaches may be helpful in assaying non-genotyped, rare causal variants. In this study, we investigated the use of two-marker haplotypes for risk prediction in Crohn's disease and show that it leads to improved prediction accuracy compared with single-point analyses. With large numbers of predictors, traditional classification methods such as logistic regression and support vector machine approaches may be suboptimal. An alternative approach is to apply the risk-score method calculated as the number of risk haplotypes an individual carries, both within and across loci. We used the area under the curve (AUC) of the receiver operating curve to assess the performance of prediction models in large-scale genetic data, and observed that the prediction performance in the validation cohort continues to improve as thousands of haplotypes are included in the model, with the AUC reaching its plateau at 0.72 at ?7000 haplotypes, and begins to gradually decline after that point. In contrast, using the SNP as predictors, we only obtained maximum AUC of 0.65. Validation studies in independent cohorts further support improved prediction capacity with multi-marker, as opposed to single marker analyses.

SUBMITTER: Kang J

PROVIDER: S-EPMC3298027 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Improved risk prediction for Crohn's disease with a multi-locus approach.

Kang Jia J Kugathasan Subra S Georges Michel M Zhao Hongyu H Cho Judy H JH

Human molecular genetics 20110322 12

Genome-wide association studies have identified numerous loci demonstrating genome-wide significant association with Crohn's disease. However, when many single nucleotide polymorphisms (SNPs) have weak-to-moderate disease risks, genetic risk prediction models based only on those markers that pass the most stringent statistical significance testing threshold may be suboptimal. Haplotype-based predictive models may provide advantages over single-SNP approaches by facilitating detection of associat ...[more]

PMID: 21427131

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Project description:Risk alleles for complex diseases are widely spread throughout human populations. However, little is known about the geographic distribution and frequencies of risk alleles, which may contribute to differences in disease susceptibility and prevalence among populations. Here, we focus on Crohn's disease (CD) as a model for the evolutionary study of complex disease alleles. Recent genome-wide association studies and classical linkage analyses have identified more than 70 susceptible genomic regions for CD in Europeans, but only a few have been confirmed in non-European populations. Our analysis of eight European-specific susceptibility genes using HapMap data shows that at the NOD2 locus the CD-risk alleles are linked with a haplotype specific to CEU at a frequency that is significantly higher compared with the entire genome. We subsequently examined nine global populations and found that the CD-risk alleles spread through hitchhiking with a high-frequency haplotype (H1) exclusive to Europeans. To examine the neutrality of NOD2, we performed phylogenetic network analyses, coalescent simulation, protein structural prediction, characterization of mutation patterns, and estimations of population growth and time to most recent common ancestor (TMRCA). We found that while H1 was significantly prevalent in European populations, the H1 TMRCA predated human migration out of Africa. H1 is likely to have undergone negative selection because 1) the root of H1 genealogy is defined by a preexisting amino acid substitution that causes serious conformational changes to the NOD2 protein, 2) the haplotype has almost become extinct in Africa, and 3) the haplotype has not been affected by the recent European expansion reflected in the other haplotypes. Nevertheless, H1 has survived in European populations, suggesting that the haplotype is advantageous to this group. We propose that several CD-risk alleles, which destabilize and disrupt the NOD2 protein, have been maintained by natural selection on standing variation because the deleterious haplotype of NOD2 is advantageous in diploid individuals due to heterozygote advantage and/or intergenic interactions.

Dataset Information

Improved risk prediction for Crohn's disease with a multi-locus approach.

Publications

Improved risk prediction for Crohn's disease with a multi-locus approach.

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