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.
authors: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: S P
authors: SP
authors: Kar
authors: M F
authors: MF
authors: Seldin
authors: W
authors: W
authors: Chen
authors: E
authors: E
authors: Lu
authors: G M
authors: GM
authors: Hirschfield
authors: P
authors: P
authors: Invernizzi
authors: J
authors: J
authors: Heathcote
authors: D
authors: D
authors: Cusi
authors: M E
authors: ME
authors: Gershwin
authors: K A
authors: KA
authors: Siminovitch
authors: C I
authors: CI
authors: Amos
mesh_terms: D000465:Algorithms; D002170:Canada; D015331:Cohort Studies; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D008105:Liver Cirrhosis, Biliary / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics*
references: Gut. 2007 Nov;56(11):1615-24
references: 17641080
references: Hepatology. 2009 Mar;49(3):871-9
references: 19185000
references: J Hepatol. 1999 Mar;30(3):402-7
references: 10190721
references: Genes Immun. 2005 Oct;6(7):543-56
references: 16034472
references: Nat Genet. 2010 Aug;42(8):658-60
references: 20639880
references: Hepatology. 2005 Nov;42(5):1194-202
references: 16250040
references: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11382-7
references: 17585010
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: J Clin Invest. 2008 Oct;118(10):3331-42
references: 18802480
references: Hepatology. 2009 Aug;50(2):518-27
references: 19575365
references: Hepatology. 2009 Nov;50(5):1347-50
references: 19876938
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W90-5
references: 20435672
references: Nat Genet. 2010 Aug;42(8):655-7
references: 20639879
references: Nature. 2009 Sep 10;461(7261):218-23
references: 19741703
references: Hepatology. 2007 Apr;45(4):977-81
references: 17393507
references: J Biol Chem. 2006 Jun 9;281(23):16128-38
references: 16527821
references: Nat Genet. 2010 Jul;42(7):570-5
references: 20562874
references: PLoS One. 2012;7(1):e29396
references: 22238607
references: Hepatology. 2009 Jul;50(1):291-308
references: 19554543
references: Am J Hum Genet. 2010 Jan;86(1):6-22
references: 20074509
references: J Autoimmun. 2011 May;36(3-4):278-87
references: 21396797
references: J Immunol. 2011 Sep 1;187(5):2376-85
references: 21810603
references: PLoS One. 2010 Nov 15;5(11):e13950
references: 21085570
references: Allergy. 2009 May;64(5):702-9
references: 19383026
references: Gut. 2008 Sep;57(9):1275-82
references: 18375471
references: Nat Immunol. 2003 Apr;4(4):313-9
references: 12660731
references: Am J Hum Genet. 2007 Dec;81(6):1278-83
references: 17966091
references: Cell Signal. 2011 May;23(5):866-75
references: 21262348
references: Dig Liver Dis. 2010 Jun;42(6):401-8
references: 20359968
references: Gastroenterology. 2004 Aug;127(2):485-92
references: 15300581
references: Semin Liver Dis. 2007 May;27(2):161-72
references: 17520516
references: Nat Rev Genet. 2010 Dec;11(12):843-54
references: 21085203
references: Nat Rev Immunol. 2007 Mar;7(3):191-201
references: 17290298
references: N Engl J Med. 2009 Jun 11;360(24):2544-55
references: 19458352
references: Hepatology. 2007 May;45(5):1091-6
references: 17464985
references: Gut. 2001 Oct;49(4):565-76
references: 11559656
references: BMC Res Notes. 2011 Oct 07;4:386
references: 21981765
references: Nat Genet. 2011 Mar 13;43(4):329-32
references: 21399635
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Nat Rev Genet. 2008 May;9(5):356-69
references: 18398418
references: Cell. 2001 Feb 23;104(4):487-501
references: 11239407
references: Science. 2004 Jun 18;304(5678):1755-9
references: 15205520
references: Eur J Hum Genet. 2010 Sep;18(9):1045-53
references: 20442747
references: PLoS One. 2011;6(8):e23899
references: 21909376
references: J Biol Chem. 2011 Oct 28;286(43):37732-40
references: 21908606
references: J Immunol. 2009 May 1;182(9):5225-31
references: 19380768