Fine-mapping inflammatory bowel disease loci to single-variant resolution

Hailiang Huang, Ming Fang, Luke Jostins, Maša Umićević Mirkov, Gabrielle Boucher, Carl A Anderson, Vibeke Andersen, Isabelle Cleynen, Adrian Cortes, François Crins, Mauro D'Amato, Valérie Deffontaine, Julia Dmitrieva, Elisa Docampo, Mahmoud Elansary, Kyle Kai-How Farh, Andre Franke, Ann-Stephan Gori, Philippe Goyette, Jonas Halfvarson & 27 andre Talin Haritunians, Jo Knight, Ian C Lawrance, Charlie W Lees, Edouard Louis, Rob Mariman, Theo Meuwissen, Myriam Mni, Yukihide Momozawa, Miles Parkes, Sarah L Spain, Emilie Théâtre, Gosia Trynka, Jack Satsangi, Suzanne van Sommeren, Severine Vermeire, Ramnik J Xavier, Rinse K Weersma, Richard H Duerr, Christopher G Mathew, John D Rioux, Dermot P B McGovern, Judy H Cho, Michel Georges, Mark J Daly, Jeffrey C Barrett, International Inflammatory Bowel Disease Genetics Consortium

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Resumé

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind547
Udgave nummer7662
Sider (fra-til)173-178
ISSN0028-0836
DOI
StatusUdgivet - 13. jul. 2017

Fingeraftryk

Inflammatory Bowel Diseases
Genome-Wide Association Study
Ulcerative Colitis
Epigenomics
Crohn Disease
Mucous Membrane
Proteins

Citer dette

Huang, H., Fang, M., Jostins, L., Umićević Mirkov, M., Boucher, G., Anderson, C. A., ... International Inflammatory Bowel Disease Genetics Consortium (2017). Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature, 547(7662), 173-178. https://doi.org/10.1038/nature22969
Huang, Hailiang ; Fang, Ming ; Jostins, Luke ; Umićević Mirkov, Maša ; Boucher, Gabrielle ; Anderson, Carl A ; Andersen, Vibeke ; Cleynen, Isabelle ; Cortes, Adrian ; Crins, François ; D'Amato, Mauro ; Deffontaine, Valérie ; Dmitrieva, Julia ; Docampo, Elisa ; Elansary, Mahmoud ; Farh, Kyle Kai-How ; Franke, Andre ; Gori, Ann-Stephan ; Goyette, Philippe ; Halfvarson, Jonas ; Haritunians, Talin ; Knight, Jo ; Lawrance, Ian C ; Lees, Charlie W ; Louis, Edouard ; Mariman, Rob ; Meuwissen, Theo ; Mni, Myriam ; Momozawa, Yukihide ; Parkes, Miles ; Spain, Sarah L ; Théâtre, Emilie ; Trynka, Gosia ; Satsangi, Jack ; van Sommeren, Suzanne ; Vermeire, Severine ; Xavier, Ramnik J ; Weersma, Rinse K ; Duerr, Richard H ; Mathew, Christopher G ; Rioux, John D ; McGovern, Dermot P B ; Cho, Judy H ; Georges, Michel ; Daly, Mark J ; Barrett, Jeffrey C ; International Inflammatory Bowel Disease Genetics Consortium. / Fine-mapping inflammatory bowel disease loci to single-variant resolution. I: Nature. 2017 ; Bind 547, Nr. 7662. s. 173-178.
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abstract = "Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95{\%} certainty, and an additional 27 associations to a single variant with greater than 50{\%} certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.",
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Huang, H, Fang, M, Jostins, L, Umićević Mirkov, M, Boucher, G, Anderson, CA, Andersen, V, Cleynen, I, Cortes, A, Crins, F, D'Amato, M, Deffontaine, V, Dmitrieva, J, Docampo, E, Elansary, M, Farh, KK-H, Franke, A, Gori, A-S, Goyette, P, Halfvarson, J, Haritunians, T, Knight, J, Lawrance, IC, Lees, CW, Louis, E, Mariman, R, Meuwissen, T, Mni, M, Momozawa, Y, Parkes, M, Spain, SL, Théâtre, E, Trynka, G, Satsangi, J, van Sommeren, S, Vermeire, S, Xavier, RJ, Weersma, RK, Duerr, RH, Mathew, CG, Rioux, JD, McGovern, DPB, Cho, JH, Georges, M, Daly, MJ, Barrett, JC & International Inflammatory Bowel Disease Genetics Consortium 2017, 'Fine-mapping inflammatory bowel disease loci to single-variant resolution', Nature, bind 547, nr. 7662, s. 173-178. https://doi.org/10.1038/nature22969

Fine-mapping inflammatory bowel disease loci to single-variant resolution. / Huang, Hailiang; Fang, Ming; Jostins, Luke; Umićević Mirkov, Maša; Boucher, Gabrielle; Anderson, Carl A; Andersen, Vibeke; Cleynen, Isabelle; Cortes, Adrian; Crins, François; D'Amato, Mauro; Deffontaine, Valérie; Dmitrieva, Julia; Docampo, Elisa; Elansary, Mahmoud; Farh, Kyle Kai-How; Franke, Andre; Gori, Ann-Stephan; Goyette, Philippe; Halfvarson, Jonas; Haritunians, Talin; Knight, Jo; Lawrance, Ian C; Lees, Charlie W; Louis, Edouard; Mariman, Rob; Meuwissen, Theo; Mni, Myriam; Momozawa, Yukihide; Parkes, Miles; Spain, Sarah L; Théâtre, Emilie; Trynka, Gosia; Satsangi, Jack; van Sommeren, Suzanne; Vermeire, Severine; Xavier, Ramnik J; Weersma, Rinse K; Duerr, Richard H; Mathew, Christopher G; Rioux, John D; McGovern, Dermot P B; Cho, Judy H; Georges, Michel; Daly, Mark J; Barrett, Jeffrey C; International Inflammatory Bowel Disease Genetics Consortium.

I: Nature, Bind 547, Nr. 7662, 13.07.2017, s. 173-178.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Fine-mapping inflammatory bowel disease loci to single-variant resolution

AU - Huang, Hailiang

AU - Fang, Ming

AU - Jostins, Luke

AU - Umićević Mirkov, Maša

AU - Boucher, Gabrielle

AU - Anderson, Carl A

AU - Andersen, Vibeke

AU - Cleynen, Isabelle

AU - Cortes, Adrian

AU - Crins, François

AU - D'Amato, Mauro

AU - Deffontaine, Valérie

AU - Dmitrieva, Julia

AU - Docampo, Elisa

AU - Elansary, Mahmoud

AU - Farh, Kyle Kai-How

AU - Franke, Andre

AU - Gori, Ann-Stephan

AU - Goyette, Philippe

AU - Halfvarson, Jonas

AU - Haritunians, Talin

AU - Knight, Jo

AU - Lawrance, Ian C

AU - Lees, Charlie W

AU - Louis, Edouard

AU - Mariman, Rob

AU - Meuwissen, Theo

AU - Mni, Myriam

AU - Momozawa, Yukihide

AU - Parkes, Miles

AU - Spain, Sarah L

AU - Théâtre, Emilie

AU - Trynka, Gosia

AU - Satsangi, Jack

AU - van Sommeren, Suzanne

AU - Vermeire, Severine

AU - Xavier, Ramnik J

AU - Weersma, Rinse K

AU - Duerr, Richard H

AU - Mathew, Christopher G

AU - Rioux, John D

AU - McGovern, Dermot P B

AU - Cho, Judy H

AU - Georges, Michel

AU - Daly, Mark J

AU - Barrett, Jeffrey C

AU - International Inflammatory Bowel Disease Genetics Consortium

PY - 2017/7/13

Y1 - 2017/7/13

N2 - Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

AB - Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

KW - Journal Article

U2 - 10.1038/nature22969

DO - 10.1038/nature22969

M3 - Journal article

VL - 547

SP - 173

EP - 178

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7662

ER -

Huang H, Fang M, Jostins L, Umićević Mirkov M, Boucher G, Anderson CA et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature. 2017 jul 13;547(7662):173-178. https://doi.org/10.1038/nature22969