title: A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients.
abstract: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.
  
  
  
  Subjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study (GWAS) approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.
  
  
  
  Nineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 (10/9, PBC/PSC) SNPs reached a stringent (corrected) significance threshold and a further 21 (9/12, PBC/PSC) reached a nominal level of significance (P < 0.05 with odds ratio (OR) > 1.2 or < 0.83), providing suggestive evidence of association. The SNPs mapped to seven (1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33) and one (6p21) chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter (P = 1.2 × 10-5, OR = 0.39) demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene (P = 0.0095, OR = 0.2) and rs3822659 (P = 0.0051, OR = 0.236) along with rs9686714 (P = 0.00077, OR = 0.2), both located in the WWC1 gene.
  
  
  
  Our cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and/or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Paziewska
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Habior
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rogowska
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Włodzimierz
authors.initials: W
authors.lastname: Zych
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Goryca
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Karczmarski
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Michalina
authors.initials: M
authors.lastname: Dabrowska
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
authors.forename: Filip
authors.initials: F
authors.lastname: Ambrozkiewicz
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Bozena
authors.initials: B
authors.lastname: Walewska-Zielecka
authors.affiliation: Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Krawczyk
authors.affiliation: Department of Gastroenterology, Medical University, Lublin, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Cichoz-Lach
authors.affiliation: Department of General, Liver and Internal Medicine Unit, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.|Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Milkiewicz
authors.affiliation: Department of Gastroenterology, Medical University, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kowalik
authors.affiliation: Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.|Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Mucha
authors.affiliation: Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Raczynska
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Musialik
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Boryczka
authors.affiliation: Department of General, Liver and Internal Medicine Unit, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Wasilewicz
authors.affiliation: Department of Gastroenterology and Infectious Diseases, Collegium Medicum Jagiellonian University, Krakow, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Ciecko-Michalska
authors.affiliation: Department of Gastroenterology, Provincial Hospital, Olsztyn, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Ferenc
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Janiak
authors.affiliation: Department of Internal and Metabolic Diseases and Dietetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Alina
authors.initials: A
authors.lastname: Kanikowska
authors.affiliation: Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Rafal
authors.initials: R
authors.lastname: Stankiewicz
authors.affiliation: Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Hartleb
authors.affiliation: Department of Gastroenterology and Infectious Diseases, Collegium Medicum Jagiellonian University, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Mach
authors.affiliation: Department of Internal and Metabolic Diseases and Dietetics, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Marian
authors.initials: M
authors.lastname: Grzymislawski
authors.affiliation: Department of General, Liver and Internal Medicine Unit, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Raszeja-Wyszomirska
authors.affiliation: Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wunsch
authors.affiliation: Department of Gastroenterology, Provincial Hospital, Ostroleka, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bobinski
authors.affiliation: Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
authors.forename: Michal
authors.initials: M
authors.lastname: Mikula
authors.affiliation: Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow@warman.com.pl.|Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland. jostrow@warman.com.pl.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ostrowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D015209:Cholangitis, Sclerosing / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
keywords: Genome-wide association study; Primary biliary cholangitis; Primary sclerosing cholangitis