Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Jimmy Z Liu; Mohamed A Almarri; Daniel J Gaffney; George F Mells; Luke Jostins; Heather J Cordell; Samantha J Ducker; Darren B Day; Michael A Heneghan; James M Neuberger; Peter T Donaldson; Andrew J Bathgate; Andrew Burroughs; Mervyn H Davies; David E Jones; Graeme J Alexander; Jeffrey C Barrett; Richard N Sandford; Carl A Anderson; UK Primary Biliary Cirrhosis (PBC) Consortium

doi:10.1038/ng.2395

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Jimmy Z Liu, Mohamed A Almarri, Daniel J Gaffney, George F Mells, Luke Jostins, Heather J Cordell, Samantha J Ducker, Darren B Day, Michael A Heneghan, James M Neuberger, Peter T Donaldson, Andrew J Bathgate, Andrew Burroughs, Mervyn H Davies, David E Jones, Graeme J Alexander, Jeffrey C Barrett, Richard N Sandford, Carl A Anderson, UK Primary Biliary Cirrhosis (PBC) Consortium

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

175 Citations (Scopus)

Abstract

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

Original language	English
Pages (from-to)	1137-41
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	10
DOIs	https://doi.org/10.1038/ng.2395
Publication status	Published - Oct 2012

Keywords

Case-Control Studies
Chromosome Mapping
Chromosomes, Human, Pair 19
Gene Frequency
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
HLA Antigens
Humans
Linkage Disequilibrium
Liver Cirrhosis, Biliary
Polymorphism, Single Nucleotide
Proteins
Regression Analysis
Sequence Analysis, DNA
TYK2 Kinase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2395

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Liu, J. Z., Almarri, M. A., Gaffney, D. J., Mells, G. F., Jostins, L., Cordell, H. J., Ducker, S. J., Day, D. B., Heneghan, M. A., Neuberger, J. M., Donaldson, P. T., Bathgate, A. J., Burroughs, A., Davies, M. H., Jones, D. E., Alexander, G. J., Barrett, J. C., Sandford, R. N., Anderson, C. A., & UK Primary Biliary Cirrhosis (PBC) Consortium (2012). Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nature Genetics, 44(10), 1137-41. https://doi.org/10.1038/ng.2395

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abstract = "We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.",

keywords = "Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 19, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA Antigens, Humans, Linkage Disequilibrium, Liver Cirrhosis, Biliary, Polymorphism, Single Nucleotide, Proteins, Regression Analysis, Sequence Analysis, DNA, TYK2 Kinase",

author = "Liu, {Jimmy Z} and Almarri, {Mohamed A} and Gaffney, {Daniel J} and Mells, {George F} and Luke Jostins and Cordell, {Heather J} and Ducker, {Samantha J} and Day, {Darren B} and Heneghan, {Michael A} and Neuberger, {James M} and Donaldson, {Peter T} and Bathgate, {Andrew J} and Andrew Burroughs and Davies, {Mervyn H} and Jones, {David E} and Alexander, {Graeme J} and Barrett, {Jeffrey C} and Sandford, {Richard N} and Anderson, {Carl A} and {UK Primary Biliary Cirrhosis (PBC) Consortium}",

year = "2012",

month = oct,

doi = "10.1038/ng.2395",

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Liu, JZ, Almarri, MA, Gaffney, DJ, Mells, GF, Jostins, L, Cordell, HJ, Ducker, SJ, Day, DB, Heneghan, MA, Neuberger, JM, Donaldson, PT, Bathgate, AJ, Burroughs, A, Davies, MH, Jones, DE, Alexander, GJ, Barrett, JC, Sandford, RN, Anderson, CA & UK Primary Biliary Cirrhosis (PBC) Consortium 2012, 'Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis', Nature Genetics, vol. 44, no. 10, pp. 1137-41. https://doi.org/10.1038/ng.2395

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AU - Liu, Jimmy Z

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AU - Gaffney, Daniel J

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AU - Jostins, Luke

AU - Cordell, Heather J

AU - Ducker, Samantha J

AU - Day, Darren B

AU - Heneghan, Michael A

AU - Neuberger, James M

AU - Donaldson, Peter T

AU - Bathgate, Andrew J

AU - Burroughs, Andrew

AU - Davies, Mervyn H

AU - Jones, David E

AU - Alexander, Graeme J

AU - Barrett, Jeffrey C

AU - Sandford, Richard N

AU - Anderson, Carl A

AU - UK Primary Biliary Cirrhosis (PBC) Consortium

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N2 - We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

AB - We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r2>0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

KW - Case-Control Studies

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 19

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - HLA Antigens

KW - Humans

KW - Linkage Disequilibrium

KW - Liver Cirrhosis, Biliary

KW - Polymorphism, Single Nucleotide

KW - Proteins

KW - Regression Analysis

KW - Sequence Analysis, DNA

KW - TYK2 Kinase

U2 - 10.1038/ng.2395

DO - 10.1038/ng.2395

M3 - Article

C2 - 22961000

SN - 1061-4036

VL - 44

SP - 1137

EP - 1141

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

Abstract

Keywords

UN SDGs

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