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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10^-8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

SUBMITTER: Ishigaki K

PROVIDER: S-EPMC10165422 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Ishigaki Kazuyoshi K Sakaue Saori S Terao Chikashi C Luo Yang Y Sonehara Kyuto K Yamaguchi Kensuke K Amariuta Tiffany T Too Chun Lai CL Laufer Vincent A VA Scott Ian C IC Viatte Sebastien S Takahashi Meiko M Ohmura Koichiro K Murasawa Akira A Hashimoto Motomu M Ito Hiromu H Hammoudeh Mohammed M Emadi Samar Al SA Masri Basel K BK Halabi Hussein H Badsha Humeira H Uthman Imad W IW Wu Xin X Lin Li L Li Ting T Plant Darren D Barton Anne A Orozco Gisela G Verstappen Suzanne M M SMM Bowes John J MacGregor Alexander J AJ Honda Suguru S Koido Masaru M Tomizuka Kohei K Kamatani Yoichiro Y Tanaka Hiroaki H Tanaka Eiichi E Suzuki Akari A Maeda Yuichi Y Yamamoto Kenichi K Miyawaki Satoru S Xie Gang G Zhang Jinyi J Amos Christopher I CI Keystone Edward E Wolbink Gertjan G van der Horst-Bruinsma Irene I Cui Jing J Liao Katherine P KP Carroll Robert J RJ Lee Hye-Soon HS Bang So-Young SY Siminovitch Katherine A KA de Vries Niek N Alfredsson Lars L Rantapää-Dahlqvist Solbritt S Karlson Elizabeth W EW Bae Sang-Cheol SC Kimberly Robert P RP Edberg Jeffrey C JC Mariette Xavier X Huizinga Tom T Dieudé Philippe P Schneider Matthias M Kerick Martin M Denny Joshua C JC Matsuda Koichi K Matsuo Keitaro K Mimori Tsuneyo T Matsuda Fumihiko F Fujio Keishi K Tanaka Yoshiya Y Kumanogoh Atsushi A Traylor Matthew M Lewis Cathryn M CM Eyre Stephen S Xu Huji H Saxena Richa R Arayssi Thurayya T Kochi Yuta Y Ikari Katsunori K Harigai Masayoshi M Gregersen Peter K PK Yamamoto Kazuhiko K Louis Bridges S S Padyukov Leonid L Martin Javier J Klareskog Lars L Okada Yukinori Y Raychaudhuri Soumya S

Nature genetics 20221104 11

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10<sup>-8</sup>), of which 34 are nove ...[more]

PMID: 36333501

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Project description:BackgroundAsthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression.MethodsA meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico.ResultsOne hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele = 0.85, p = 3.10 × 10-5 and replication: ORC allele = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood.ConclusionsThis multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Dataset Information

Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Publications

Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

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