title: Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.
abstract: Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor.
  
  
  CONCLUSIONS
  By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis.
authors: Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
authors: David
authors: D
authors: Ellinghaus
authors: Trine
authors: T
authors: Folseraas
authors: Kristian
authors: K
authors: Holm
authors: Eva
authors: E
authors: Ellinghaus
authors: Espen
authors: E
authors: Melum
authors: Tobias
authors: T
authors: Balschun
authors: Jon K
authors: JK
authors: Laerdahl
authors: Alexey
authors: A
authors: Shiryaev
authors: Daniel N
authors: DN
authors: Gotthardt
authors: Tobias J
authors: TJ
authors: Weismüller
authors: Christoph
authors: C
authors: Schramm
authors: Michael
authors: M
authors: Wittig
authors: Annika
authors: A
authors: Bergquist
authors: Einar
authors: E
authors: Björnsson
authors: Hanns-Ulrich
authors: HU
authors: Marschall
authors: Morten
authors: M
authors: Vatn
authors: Andreas
authors: A
authors: Teufel
authors: Christian
authors: C
authors: Rust
authors: Christian
authors: C
authors: Gieger
authors: H-Erich
authors: HE
authors: Wichmann
authors: Heiko
authors: H
authors: Runz
authors: Martina
authors: M
authors: Sterneck
authors: Christian
authors: C
authors: Rupp
authors: Felix
authors: F
authors: Braun
authors: Rinse K
authors: RK
authors: Weersma
authors: Cisca
authors: C
authors: Wijmenga
authors: Cyriel Y
authors: CY
authors: Ponsioen
authors: Christopher G
authors: CG
authors: Mathew
authors: Paul
authors: P
authors: Rutgeerts
authors: Séverine
authors: S
authors: Vermeire
authors: Erik
authors: E
authors: Schrumpf
authors: Johannes R
authors: JR
authors: Hov
authors: Michael P
authors: MP
authors: Manns
authors: Kirsten M
authors: KM
authors: Boberg
authors: Stefan
authors: S
authors: Schreiber
authors: Andre
authors: A
authors: Franke
authors: Tom H
authors: TH
authors: Karlsen
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D001530:Belgium; D016022:Case-Control Studies; D015209:Cholangitis, Sclerosing / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D015897:Comorbidity; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005858:Germany; D006801:Humans; D009426:Netherlands; D009664:Norway; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D012307:Risk Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C111379:GPR35 protein, human; D043562:Receptors, G-Protein-Coupled; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors