一个高分辨率 HLA 参考面板，捕获全球人群多样性，可实现 HIV 宿主反应中的多祖源精细映射。

A high-resolution HLA reference panel capturing global population diversity enables multi-ancestry fine-mapping in HIV host response.

机构信息

Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Division of Rheumatology, Immunology, and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

出版信息

Nat Genet. 2021 Oct;53(10):1504-1516. doi: 10.1038/s41588-021-00935-7. Epub 2021 Oct 5.

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.

精细映射到可能的因果变异可能在多祖裔队列中更有效，特别是在 MHC 中，它具有特定于群体的结构。为了能够进行此类研究，我们构建了一个基于全基因组序列的大型（n=21546）HLA 参考面板，涵盖了五个全球人群。尽管存在特定于群体的长程单倍型，但我们在 G 组分辨率（混合非洲裔（AA）、东亚裔（EAS）、欧洲裔（EUR）和拉丁裔（LAT）人群中的准确性分别为 94.2%、93.7%、97.8%和 93.7%）上实现了准确的推断。我们将 HLA 推断应用于三个人群（EUR、AA 和 LAT）的 HIV-1 病毒载量全基因组关联研究数据中，消除了先前报道的来自特定于人群的 HIV 研究的关联，并在 HLA-B 的位置 156 发现了一个新的关联。我们将 MHC 关联精确定位到 HLA-B 肽结合槽内的三个氨基酸位置（97、67 和 156），标记三个连续的口袋（C、B 和 D），解释了 12.9%的性状方差。