Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

Franke, André; McGovern, Dermot; Barrett, Jeffrey C.; Wang, Kai; Radford‐Smith, Graham; Ahmad, Tariq; Lees, Charlie W; Balschun, Tobias; Lee, James; Roberts, Rebecca; Anderson, Carl A.; Bis, Joshua C.; Bumpstead, S. J.; Ellinghaus, David; Festen, Eleonora M.; Georges, Michel; Green, Todd; Haritunians, Talin; Jostins, Luke; Latiano, Anna; Mathew, Christopher G.; Montgomery, Grant W.; Prescott, Natalie J.; Raychaudhuri, Soumya; Rotter, Jerome I.; Schumm, L. Philip; Sharma, Yashoda; Simms, Lisa A.; Taylor, Kent D.; Whiteman, David C.; Wijmenga, Cisca; Baldassano, Robert N.; Barclay, Murray L.; Bayless, Theodore M.; Brand, Stephan; Büning, Carsten; Cohen, Albert; Colombel, Jean Frederick; Cottone, Mario; Stronati, Laura; Denson, Ted; Vos, Martine De; D’Incà, R.; Dubinsky, Marla; Edwards, Cathryn; Florin, Tim; Franchimont, Denis; Gearry, Richard B.; Glas, Jürgen; Gossum, A. Van; Guthery, Stephen L.; Halfvarson, Jonas; Verspaget, Hein W.; Hugot, Jean‐Pierre; Karban, Amir; Laukens, Debby; Lawrance, Ian C.; Lémann, Marc; Levine, Arie; Libioulle, Cécile; Louis, Édouard; Mowat, Craig; Newman, William G.; Panés, Julián; Phillips, Anne; Proctor, Deborah D.; Regueiro, Miguel; Russell, Richard K.; Rutgeerts, Paul; Sanderson, Jeremy; Sans, Miquel; Seibold, Frank; Steinhart, A. Hillary; Stokkers, Pieter; Törkvist, Leif; Kullak‐Ublick, Gerd A.; Wilson, David C.; Walters, Thomas D.; Targan, Stephan R.; Brant, Steven R.; Rioux, John D.; D’Amato, Mauro; Weersma, Rinse K.; Kugathasan, Subra; Griffiths, Anne M.; Mansfield, John C.; Vermeire, Séverine; Duerr, Richard H.; Silverberg, Mark S.; Satsangi, Jack; Schreiber, Stefan; Cho, Judy H.; Annese, Vito; Hákonarson, Hákon; Daly, Mark J.; Parkes, Miles

doi:10.1038/ng.717

Cited by 2,308 publications

(2,020 citation statements)

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“…As the identification of NOD2/CARD15 as the first susceptibility gene for CD, an intriguing hypothesis was raised, suggesting that genetic variations in other receptors of the innate immune system may contribute to CD susceptibility. Genome-wide association studies have identified multiple susceptibility loci involved in the genetic susceptibility to CD, 23,24 and they have confirmed the main role of the innate immunity in the disease. However, these loci explain about only the 10% of the overall variance in disease risk, which may be as much as a fifth of the genetic risk, suggesting that many additional loci are yet to be identified.…”

Section: Discussionmentioning

confidence: 87%

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

et al. 2011

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Impaired innate inflammatory response has a key role in the Crohn's disease (CD) pathogenesis. The aim of this study was to investigate the possible role of the TLR10-TLR1-TLR6 gene cluster in CD susceptibility. A total of 508 CD patients (284, cohort 1 and 224, cohort 2) and 576 controls were included. TLR10-TLR1-TLR6 cluster single-nucleotide polymorphisms genotyping, NOD2 mutations and TLR10 mRNA quantification were performed using TaqMan assays. Nucleotide-binding oligomerization domain containing 2 (NOD2) and Toll-like receptor (TLR) loci interaction was analyzed by logistic regression and multifactor-dimensionality reduction (MDR). Entropy-based analysis was used to interpret combination effects. One TLR10 haplotype (TLR10 GGGG ) was found associated with CD susceptibility in both cohorts, individuals with two copies had approximately twofold more risk of CD susceptibility than individuals having no copies (odds ratio ¼ 1.89, P-value ¼ 0.0002). No differences in the mRNA levels were observed among the genotypes. The strongest model for predicting CD risk according to the MDR analysis was a two-locus model including NOD2 mutations and TLR10 GGGG haplotype (P c o0.0001). The interaction gain attributed to the combination of both genes was negative (IG ¼ À2.36%), indicating redundancy or independent effects. Our results support association of the TLR10 gene with CD susceptibility. The effect of TLR10 would be independent of NOD2, suggesting different signaling pathways for both genes.

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Section: Discussionmentioning

confidence: 87%

Association of Toll-like receptor 10 and susceptibility to Crohn's disease independent of NOD2

et al. 2011

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“…3 Therefore, large sample sizes are required and many collaborations have been established to achieve this, resulting in published metaanalyses for a range of diseases and traits. [4][5][6][7][8] One standard quality-control measure for GWAS and meta-analysis is genomic control (GC). [9][10][11] The concept behind this method is that apart from a small number of SNPs that show a true association with the trait or disease, the test statistics for other SNPs should follow the distribution under the null hypothesis of no association between a SNP and the trait.…”

Section: Introductionmentioning

confidence: 99%

Genomic inflation factors under polygenic inheritance

Yang

Weedon²,

Purcell³

et al. 2011

Eur J Hum Genet

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Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple singlenucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of B4000 and B133 000 individuals.

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“…A growing body of genetic associations in Crohn's disease (CD) and ulcerative colitis (UC) have identified polymorphisms in or near genes central to CD4? T cell function, such as the receptor for interleukin (IL)-23 [1], a cytokine essential for the survival of the Th17 subset of CD4? T cells, which is implicated in the pathogenesis of several animal models of autoimmunity [2].…”

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confidence: 99%