Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.
Manuel A. Rivas,Manuel A. Rivas,Manuel A. Rivas,Mélissa Beaudoin,Agnes Gardet,Christine Stevens,Yashoda Sharma,Clarence K. Zhang,Gabrielle Boucher,Stephan Ripke,Stephan Ripke,David Ellinghaus,Noël P. Burtt,Timothy Fennell,Andrew Kirby,Andrew Kirby,Anna Latiano,Philippe Goyette,Todd Green,Jonas Halfvarson,Talin Haritunians,Joshua M. Korn,Finny G Kuruvilla,Caroline Lagacé,Benjamin M. Neale,Benjamin M. Neale,Ken Sin Lo,Phil Schumm,Leif Törkvist,Marla Dubinsky,Steven R. Brant,Mark S. Silverberg,Richard H. Duerr,David Altshuler,David Altshuler,Stacey Gabriel,Guillaume Lettre,Andre Franke,Mauro D'Amato,Dermot P.B. McGovern,Judy H. Cho,John D. Rioux,Ramnik J. Xavier,Ramnik J. Xavier,Mark J. Daly,Mark J. Daly +45 more
TLDR
Next-generation sequencing is used to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls to identify new, rare and probably functional variants that could aid functional experiments and predictive models.Abstract:
More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.read more
Citations
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Role of the Microbiota in Immunity and Inflammation
Yasmine Belkaid,Timothy W. Hand +1 more
TL;DR: In high-income countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses.
Journal ArticleDOI
Five years of GWAS discovery
Peter M. Visscher,Peter M. Visscher,Matthew A. Brown,Mark I. McCarthy,Mark I. McCarthy,Jian Yang +5 more
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Journal ArticleDOI
Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations
Jimmy Z. Liu,S van Sommeren,Hailiang Huang,Siew C. Ng,Rudi Alberts,Atsushi Takahashi,Stephan Ripke,James Lee,Luke Jostins,Tejas Shah,Shifteh Abedian,Jae Hee Cheon,Judy H. Cho,N E Dayani,Lude Franke,Yuta Fuyuno,Ailsa L. Hart,Ramesh C. Juyal,Garima Juyal,Won Ho Kim,Andrew P. Morris,Hossein Poustchi,William G. Newman,Vandana Midha,Timothy R. Orchard,H Vahedi,Ajit Sood,J Y Sung,Reza Malekzadeh,Westra H-J.,Keiko Yamazaki,Yang S-K.,Jeffrey C. Barrett,Behrooz Z. Alizadeh,Miles Parkes,T Bk,Mark J. Daly,Michiaki Kubo,Carl A. Anderson,Rinse K. Weersma +39 more
TL;DR: The first trans-ancestry association study of IBD is reported, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent, implicate 38 loci in IBD risk for the first time.
Journal ArticleDOI
The mystery of missing heritability: Genetic interactions create phantom heritability.
TL;DR: It is shown here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating “phantom heritability,” and a method for estimating heritability from isolated populations that is not inflated by genetic interactions is described.
Journal ArticleDOI
Rare and common variants: twenty arguments
TL;DR: 20 arguments for and against each of these models of the genetic basis of complex traits are reviewed and it is concluded that both classes of effect can be readily reconciled.
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