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.

Pathway-based analysis of primary biliary cirrhosis genome-wide association studies / S.P. Kar, M.F. Seldin, W. Chen, E. Lu, G.M. Hirschfield, P. Invernizzi, J. Heathcote, D. Cusi, P.L. Almasio, D. Alvaro, P. Andreone, A. Andriulli, C. Barlassina, A. Benedetti, F. Bernuzzi, I. Bianchi, M.C. Bragazzi, M. Brunetto, S. Bruno, L. Caliari, G. Casella, B. Coco, A. Colli, M. Colombo, S. Colombo, C. Cursaro, L.S. Croce, A. Crosignani, F. Donato, G. Elia, L. Fabris, A. Floreani, A. Galli, I. Grattagliano, R. Lazzari, A. Lleo, F. Macaluso, F. Marra, M. Marzioni, E. Mascia, A. Mattalia, R. Montanari, L. Morini, F. Morisco, L. Muratori, P. Muratori, G. Niro, A. Picciotto, M. Podda, P. Portincasa, D. Prati, C. Raggi, F. Rosina, S. Rossi, I. Sogno, G. Spinzi, M. Strazzabosco, S. Tarallo, M. Tarocchi, C. Tiribelli, P. Toniutto, M. Vinci, M. Zuin, M.E. Gershwin, K.A. Siminovitch, C.I. Amos. - In: GENES AND IMMUNITY. - ISSN 1466-4879. - 14:3(2013), pp. 179-186.

Pathway-based analysis of primary biliary cirrhosis genome-wide association studies

D. Cusi;C. Barlassina;A. Benedetti;F. Bernuzzi;L. Caliari;G. Casella;A. Colli;G. Elia;A. Lleo;F. Marra;M. Podda;M. Zuin;
2013

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.
linear combination test; phosphatidylinositol signaling; hedgehog signaling; autoimmune disease
Settore MED/12 - Gastroenterologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
gene20131.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.01 MB
Formato Adobe PDF
1.01 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/659868
Citazioni
  • ???jsp.display-item.citation.pmc??? 17
  • Scopus 46
  • ???jsp.display-item.citation.isi??? 41
social impact