Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci.
Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci.
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DOI：
10.1136/annrheumdis-2020-219065
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发表时间：
2021-05
影响因子：
27.4
通讯作者：
Kim K
中科院分区：
文献类型：
--
作者：
Ha E;Bae SC;Kim K
基于人群的遗传关联研究发现了近110个效应大小适中的类风湿性关节炎（RA）易感基因座，表明RA高度多基因遗传结构背后存在大量未发现的变异。在这里，我们进行了有史以来规模最大的跨祖先荟萃分析，目的是确定新的RA基因座，并更好地了解RA生物学潜在的遗传关联。全基因组RA关联汇总统计量在三个大型病例对照组，包括311 292个个体的韩国，日本和欧洲人群中使用的逆方差加权固定效应荟萃分析。使用公共组学资源进行了几次计算分析，以优先考虑因果变异和基因，RA变异相关特征（组织，途径和转录因子）以及用于RA治疗的潜在可重复利用药物。我们确定了11个新的RA易感基因座，分别解释了东亚人和欧洲人单核苷酸多态性遗传率的6.9%和1.8%，并确认了71个已知的非人类白细胞抗原（HLA）易感基因座，确定了90个独立的关联信号。RA变体优先位于各种转录因子的结合位点和细胞类型特异性转录激活组蛋白标记中，这同时突出了CD4+ T细胞激活的重要性和非免疫器官在RA发病机制中的潜在作用。基于基于基因相关性、表达相关变异和染色质相互作用，总共有615个合理的效应基因，包括批准用于RA治疗的药物的靶点和批准用于其他适应症的潜在可重复利用的药物。我们的研究结果提供了有关RA遗传病因学和变异驱动的RA发病机制的有用见解。
Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations. Genome-wide RA association summary statistics in three large case–control collections consisting of 311 292 individuals of Korean, Japanese and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritise causal variants and genes, RA variant-implicating features (tissues, pathways and transcription factors) and potentially repurposable drugs for RA treatment. We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the single-nucleotide polymorphism-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-human leukocyte antigens (HLA) susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription–activation histone marks that simultaneously highlighted the importance of CD4+ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications. Our findings provide useful insights regarding RA genetic aetiology and variant-driven RA pathogenesis.
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影响因子：
27.4
作者：
Kwon YC;Lim J;Bang SY;Ha E;Hwang MY;Yoon K;Choe JY;Yoo DH;Lee SS;Lee J;Chung WT;Kim TH;Sung YK;Shim SC;Choi CB;Jun JB;Kang YM;Shin JM;Lee YK;Cho SK;Kim BJ;Lee HS;Kim K;Bae SC
通讯作者：
Bae SC
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
2.7
作者：
COCHRAN, WG
通讯作者：
COCHRAN, WG