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A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response
Nature Genetics ( IF 31.7 ) Pub Date : 2021-10-05 , DOI: 10.1038/s41588-021-00935-7
Yang Luo 1, 2, 3, 4, 5 , Masahiro Kanai 4, 5, 6, 7, 8 , Wanson Choi 9 , Xinyi Li 10 , Saori Sakaue 1, 2, 3, 4, 5 , Kenichi Yamamoto 8, 11 , Kotaro Ogawa 8, 12 , Maria Gutierrez-Arcelus 1, 2, 3, 4, 5 , Peter K Gregersen 13 , Philip E Stuart 14 , James T Elder 14, 15 , Lukas Forer 16 , Sebastian Schönherr 16 , Christian Fuchsberger 16, 17, 18, 19 , Albert V Smith 17, 18 , Jacques Fellay 20, 21 , Mary Carrington 22, 23 , David W Haas 24, 25 , Xiuqing Guo 26 , Nicholette D Palmer 27 , Yii-Der Ida Chen 26 , Jerome I Rotter 26 , Kent D Taylor 26 , Stephen S Rich 28 , Adolfo Correa 29 , James G Wilson 30 , Sekar Kathiresan 5, 31, 32 , Michael H Cho 33 , Andres Metspalu 34 , Tonu Esko 5, 34 , Yukinori Okada 8, 35 , Buhm Han 9, 36 , , Paul J McLaren 37, 38 , Soumya Raychaudhuri 1, 2, 3, 4, 5, 39
Affiliation  

Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large (n = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance.



中文翻译:


捕捉全球人口多样性的高分辨率 HLA 参考面板可实现 HIV 宿主反应的多祖先精细绘图



对可能的因果变异进行精细映射可能在多祖先群体中更有效,特别是在具有群体特异性结构的 MHC 中。为了进行此类研究,我们基于全基因组序列构建了一个涵盖全球五个人群的大型 ( n = 21,546) HLA 参考组。尽管存在特定于人群的长程单倍型,但我们在 G 组分辨率下证明了准确的插补(在混合非洲 (AA)、东亚 (EAS)、欧洲 (EUR) 和拉丁裔中分别为 94.2%、93.7%、97.8% 和 93.7%( LAT)人口)。将 HLA 推算应用于三个人群(EUR、AA 和 LAT)中 HIV-1 病毒载量的全基因组关联研究数据,我们消除了先前报道的人群特异性 HIV 研究中关联的影响,并在 HLA 的第 156 位发现了一种新的关联-B。我们精确定位了 MHC 与 HLA-B 肽结合沟内三个连续口袋(C、B 和 D)的三个氨基酸位置(97、67 和 156)的关联,解释了 12.9% 的性状变异。

更新日期:2021-10-05
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