title: Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.
abstract: OBJECTIVE
  A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS).
  
  
  METHODS
  We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing.
  
  
  RESULTS
  Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients.
  
  
  CONCLUSIONS
  We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.forename: Philipp
authors.initials: P
authors.lastname: Rausch
authors.forename: Brian D
authors.initials: BD
authors.lastname: Juran
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: Alexey
authors.initials: A
authors.lastname: Shiryaev
authors.forename: Jon K
authors.initials: JK
authors.lastname: Laerdahl
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Weismüller
authors.forename: Daniel Nils
authors.initials: DN
authors.lastname: Gotthardt
authors.forename: Johannes Roksund
authors.initials: JR
authors.lastname: Hov
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Clausen
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Marcel
authors.initials: M
authors.lastname: Janse
authors.forename: Kirsten Muri
authors.initials: KM
authors.lastname: Boberg
authors.forename: Einar
authors.initials: E
authors.lastname: Björnsson
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cleynen
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Christian
authors.initials: C
authors.lastname: Rust
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Euijung
authors.initials: E
authors.lastname: Ryu
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.forename: Martina
authors.initials: M
authors.lastname: Sterneck
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: John F
authors.initials: JF
authors.lastname: Baines
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001646:Bile / Q000382:microbiology; D002648:Child; D002675:Child, Preschool; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000382:microbiology; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics* / Q000502:physiology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics; D012306:Risk; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D015260:Neprilysin; D053240:Receptors, Tumor Necrosis Factor, Member 14; D000097631:Galactoside 2-alpha-L-fucosyltransferase; C506028:TNFRSF14 protein, human; C436550:MMEL1 protein, human