International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Heather J Cordell; Younghun Han; George F Mells; Yafang Li; Gideon M Hirschfield; Casey S Greene; Gang Xie; Brian D Juran; Dakai Zhu; David C Qian; James A B Floyd; Katherine I Morley; Daniele Prati; Ana Lleo; Daniele Cusi; M Eric Gershwin; Carl A Anderson; Konstantinos N Lazaridis; Pietro Invernizzi; Michael F Seldin; Richard N Sandford; Christopher I Amos; Katherine A Siminovitch; Canadian-US PBC Consortium

doi:10.1038/ncomms9019

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Heather J Cordell, Younghun Han, George F Mells, Yafang Li, Gideon M Hirschfield, Casey S Greene, Gang Xie, Brian D Juran, Dakai Zhu, David C Qian, James A B Floyd, Katherine I Morley, Daniele Prati, Ana Lleo, Daniele Cusi, M Eric Gershwin, Carl A Anderson, Konstantinos N Lazaridis, Pietro Invernizzi, Michael F SeldinRichard N Sandford, Christopher I Amos, Katherine A Siminovitch, Canadian-US PBC Consortium

Immunology and Immunotherapy

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Abstract

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Original language	English
Article number	8019
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9019
Publication status	Published - 22 Sept 2015

Keywords

genome-wide
meta-analysis

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Cordell, H. J., Han, Y., Mells, G. F., Li, Y., Hirschfield, G. M., Greene, C. S., Xie, G., Juran, B. D., Zhu, D., Qian, D. C., Floyd, J. A. B., Morley, K. I., Prati, D., Lleo, A., Cusi, D., Gershwin, M. E., Anderson, C. A., Lazaridis, K. N., Invernizzi, P., ... Canadian-US PBC Consortium (2015). International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nature Communications, 6, Article 8019. https://doi.org/10.1038/ncomms9019

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title = "International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways",

abstract = "Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.",

keywords = "genome-wide, meta-analysis",

author = "Cordell, {Heather J} and Younghun Han and Mells, {George F} and Yafang Li and Hirschfield, {Gideon M} and Greene, {Casey S} and Gang Xie and Juran, {Brian D} and Dakai Zhu and Qian, {David C} and Floyd, {James A B} and Morley, {Katherine I} and Daniele Prati and Ana Lleo and Daniele Cusi and Gershwin, {M Eric} and Anderson, {Carl A} and Lazaridis, {Konstantinos N} and Pietro Invernizzi and Seldin, {Michael F} and Sandford, {Richard N} and Amos, {Christopher I} and Siminovitch, {Katherine A} and {Canadian-US PBC Consortium}",

year = "2015",

month = sep,

day = "22",

doi = "10.1038/ncomms9019",

language = "English",

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journal = "Nature Communications",

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Cordell, HJ, Han, Y, Mells, GF, Li, Y, Hirschfield, GM, Greene, CS, Xie, G, Juran, BD, Zhu, D, Qian, DC, Floyd, JAB, Morley, KI, Prati, D, Lleo, A, Cusi, D, Gershwin, ME, Anderson, CA, Lazaridis, KN, Invernizzi, P, Seldin, MF, Sandford, RN, Amos, CI, Siminovitch, KA & Canadian-US PBC Consortium 2015, 'International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways', Nature Communications, vol. 6, 8019. https://doi.org/10.1038/ncomms9019

TY - JOUR

T1 - International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

AU - Cordell, Heather J

AU - Han, Younghun

AU - Mells, George F

AU - Li, Yafang

AU - Hirschfield, Gideon M

AU - Greene, Casey S

AU - Xie, Gang

AU - Juran, Brian D

AU - Zhu, Dakai

AU - Qian, David C

AU - Floyd, James A B

AU - Morley, Katherine I

AU - Prati, Daniele

AU - Lleo, Ana

AU - Cusi, Daniele

AU - Gershwin, M Eric

AU - Anderson, Carl A

AU - Lazaridis, Konstantinos N

AU - Invernizzi, Pietro

AU - Seldin, Michael F

AU - Sandford, Richard N

AU - Amos, Christopher I

AU - Siminovitch, Katherine A

AU - Canadian-US PBC Consortium

PY - 2015/9/22

Y1 - 2015/9/22

N2 - Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

AB - Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

KW - genome-wide

KW - meta-analysis

U2 - 10.1038/ncomms9019

DO - 10.1038/ncomms9019

M3 - Article

C2 - 26394269

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 8019

ER -

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Abstract

Keywords

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