@article{1705dcac486d458991a957b81aa8c7be,
title = "Pathway-based analysis of primary biliary cirrhosis genome-wide association studies",
abstract = "Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10-4, FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.",
keywords = "autoimmune disease, hedgehog signaling, linear combination test, phosphatidylinositol signaling",
author = "{Italian PBC Genetics Study Group} and Kar, {S. P.} and Seldin, {M. F.} and W. Chen and E. Lu and Hirschfield, {G. M.} and P. Invernizzi and J. Heathcote and D. Cusi and Almasio, {Piero L.} and Domenico Alvaro and Pietro Andreone and Angelo Andriulli and Cristina Barlassina and Antonio Benedetti and Francesca Bernuzzi and Ilaria Bianchi and Bragazzi, {Maria Consiglia} and Maurizia Brunetto and Savino Bruno and Lisa Caliari and Giovanni Casella and Barbara Coco and Agostino Colli and Massimo Colombo and Silvia Colombo and Carmela Cursaro and Croce, {Lory Saveria} and Andrea Crosignani and Francesca Donato and Gianfranco Elia and Luca Fabris and Annarosa Floreani and Andrea Galli and Ignazio Grattagliano and Roberta Lazzari and Ana Lleo and Fabio Macaluso and Fabio Marra and Marco Marzioni and Elisabetta Mascia and Alberto Mattalia and Renzo Montanari and Lorenzo Morini and Filomena Morisco and Luigi Muratori and Paolo Muratori and Grazia Niro and Antonio Picciotto and Mauro Podda and Piero Portincasa",
note = "Funding Information: 1Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA; 3Division of Rheumatology, Allergy and Clinical Immunology, Department of Medicine, University of California, Davis, CA, USA; 4Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA; 5Centre for Liver Research, Institute of Biomedical Research and NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK; 6Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 7Center for Autoimmune Liver Diseases, Department of Medicine, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; 8Liver Centre, Toronto Western Hospital and Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 9Department of Medicine, Surgery and Dentistry, Universit{\`a} degli Studi di Milano, Milan, Italy; 10Genomics and Bioinformatics Unit, Fondazione Filarete, Milan, Italy; 11The members of the Italian PBC Genetics Study Group who participated are listed at the end of the article; 12Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada; 13Departments of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada and 14Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA. Correspondence: Dr CI Amos, Center for Genomic Medicine, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, 46 Centerra Parkway, Suite 330, Hanover, NH 03766, USA. E-mail: Christopher.I.Amos@Dartmouth.edu Received 14 September 2012; revised 20 November 2012; accepted 11 December 2012; published online 7 February 2013 Funding Information: This study was supported by NIH R01DK056839, NIH R01DK091823, NIH K08AR055688, Hypergenes (European Network for Genetic-Epidemiological Studies HEALTH-F4-2007-201550), Canadian Institutes for Health Research (MOP74621), the Ontario Research Fund (RE01-061), the Canadian PBC Society, a Canada Research Chair award and the Sherman Family Chair in Genomic Medicine to KAS. The authors thank C Coltescu, AL Mason, P Milkiewicz, RP Meyers, JA Odin, V Liakina, C Vincent and C Levy who assisted in recruiting cases for the Canadian-based PBC study.",
year = "2013",
month = may,
day = "1",
doi = "10.1038/gene.2013.1",
language = "English (US)",
volume = "14",
pages = "179--186",
journal = "Genes and Immunity",
issn = "1466-4879",
publisher = "Nature Publishing Group",
number = "3",
}