title: The influence of polygenic risk scores on heritability of anti-CCP level in RA.
abstract: The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Taylor
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Källberg
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Weinblatt
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Coblyn
authors.affiliation: Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Criswell
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Shadick
authors.affiliation: 1] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [3] Medical and Population Genetics Program, Chemical Biology Program, Broad Institute, Cambridge, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Plenge
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Karlson
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010456:Peptides, Cyclic / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D001323:Autoantibodies; C489339:GP2 protein, human; D058851:GPI-Linked Proteins; D015803:HLA-DR3 Antigen; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide