title: Genetic basis of autoantibody positive and negative rheumatoid arthritis risk in a multi-ethnic cohort derived from electronic health records.
abstract: Discovering and following up on genetic associations with complex phenotypes require large patient cohorts. This is particularly true for patient cohorts of diverse ancestry and clinically relevant subsets of disease. The ability to mine the electronic health records (EHRs) of patients followed as part of routine clinical care provides a potential opportunity to efficiently identify affected cases and unaffected controls for appropriate-sized genetic studies. Here, we demonstrate proof-of-concept that it is possible to use EHR data linked with biospecimens to establish a multi-ethnic case-control cohort for genetic research of a complex disease, rheumatoid arthritis (RA). In 1,515 EHR-derived RA cases and 1,480 controls matched for both genetic ancestry and disease-specific autoantibodies (anti-citrullinated protein antibodies [ACPA]), we demonstrate that the odds ratios and aggregate genetic risk score (GRS) of known RA risk alleles measured in individuals of European ancestry within our EHR cohort are nearly identical to those derived from a genome-wide association study (GWAS) of 5,539 autoantibody-positive RA cases and 20,169 controls. We extend this approach to other ethnic groups and identify a large overlap in the GRS among individuals of European, African, East Asian, and Hispanic ancestry. We also demonstrate that the distribution of a GRS based on 28 non-HLA risk alleles in ACPA+ cases partially overlaps with ACPA- subgroup of RA cases. Our study demonstrates that the genetic basis of rheumatoid arthritis risk is similar among cases of diverse ancestry divided into subsets based on ACPA status and emphasizes the utility of linking EHR clinical data with biospecimens for genetic studies.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy and Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Fina
authors.initials: F
authors.lastname: Kurreeman
authors.forename: Katherine
authors.initials: K
authors.lastname: Liao
authors.forename: Lori
authors.initials: L
authors.lastname: Chibnik
authors.forename: Brendan
authors.initials: B
authors.lastname: Hickey
authors.forename: Eli
authors.initials: E
authors.lastname: Stahl
authors.forename: Vivian
authors.initials: V
authors.lastname: Gainer
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Lynn
authors.initials: L
authors.lastname: Bry
authors.forename: Scott
authors.initials: S
authors.lastname: Mahan
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.forename: Brian
authors.initials: B
authors.lastname: Thomson
authors.forename: Peter
authors.initials: P
authors.lastname: Szolovits
authors.forename: Susanne
authors.initials: S
authors.lastname: Churchill
authors.forename: Shawn N
authors.initials: SN
authors.lastname: Murphy
authors.forename: Tianxi
authors.initials: T
authors.lastname: Cai
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Isaac
authors.initials: I
authors.lastname: Kohane
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Karlson
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D044466:Asian People / Q000235:genetics; D001323:Autoantibodies / Q000097:blood*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D057286:Electronic Health Records; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies