title: Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility loci, 1p36 and 17q12.
abstract: We have previously shown that rheumatoid arthritis (RA) risk alleles overlap between different ethnic groups. Here, we utilize a multiethnic approach to show that we can effectively discover RA risk alleles. Thirteen putatively associated SNPs that had not yet exceeded genome-wide significance (p < 5 × 10(-8)) in our previous RA genome-wide association study (GWAS) were analyzed in independent sample sets consisting of 4,366 cases and 17,765 controls of European, African American, and East Asian ancestry. Additionally, we conducted an overall association test across all 65,833 samples (a GWAS meta-analysis plus the replication samples). Of the 13 SNPs investigated, four were significantly below the study-wide Bonferroni corrected p value threshold (p < 0.0038) in the replication samples. Two SNPs (rs3890745 at the 1p36 locus [p = 2.3 × 10(-12)] and rs2872507 at the 17q12 locus [p = 1.7 × 10(-9)]) surpassed genome-wide significance in all 16,659 RA cases and 49,174 controls combined. We used available GWAS data to fine map these two loci in Europeans and East Asians, and we found that the same allele conferred risk in both ethnic groups. A series of bioinformatic analyses identified TNFRSF14-MMEL1 at the 1p36 locus and IKZF3-ORMDL3-GSDMB at the 17q12 locus as the genes most likely associated with RA. These findings demonstrate empirically that a multiethnic approach is an effective strategy for discovering RA risk loci, and they suggest that combining GWASs across ethnic groups represents an efficient strategy for gaining statistical power.
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Fina A S
authors.initials: FA
authors.lastname: Kurreeman
authors.forename: Eli A
authors.initials: EA
authors.lastname: Stahl
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Katherine
authors.initials: K
authors.lastname: Liao
authors.forename: Dorothée
authors.initials: D
authors.lastname: Diogo
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Jan
authors.initials: J
authors.lastname: Freudenberg
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Namrata
authors.initials: N
authors.lastname: Gupta
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sandor
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Kathy
authors.initials: K
authors.lastname: Siminovitch
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Laura B
authors.initials: LB
authors.lastname: Hughes
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reynolds
authors.forename: S Louis
authors.initials: SL
authors.lastname: Bridges
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000208:ethnology* / Q000235:genetics*; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D002886:Chromosomes, Human, Pair 17; D019295:Computational Biology / Q000379:methods; D005006:Ethnicity / Q000235:genetics; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D015810:Linkage Disequilibrium; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D015260:Neprilysin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics; D000094524:Gasdermins
chemical_list: D051740:Ikaros Transcription Factor; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D015260:Neprilysin; D053240:Receptors, Tumor Necrosis Factor, Member 14; C527978:GSDMB protein, human; D000094524:Gasdermins; C106285:IKZF3 protein, human; C464399:ORMDL3 protein, human; C506028:TNFRSF14 protein, human; C436550:MMEL1 protein, human