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

ABSTRACT: 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.

SUBMITTER: Luo Y

PROVIDER: S-EPMC8959399 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Luo Yang Y Kanai Masahiro M Choi Wanson W Li Xinyi X Sakaue Saori S Yamamoto Kenichi K Ogawa Kotaro K Gutierrez-Arcelus Maria M Gregersen Peter K PK Stuart Philip E PE Elder James T JT Forer Lukas L Schönherr Sebastian S Fuchsberger Christian C Smith Albert V AV Fellay Jacques J Carrington Mary M Haas David W DW Guo Xiuqing X Palmer Nicholette D ND Chen Yii-Der Ida YI Rotter Jerome I JI Taylor Kent D KD Rich Stephen S SS Correa Adolfo A Wilson James G JG Kathiresan Sekar S Cho Michael H MH Metspalu Andres A Esko Tonu T Okada Yukinori Y Han Buhm B McLaren Paul J PJ Raychaudhuri Soumya S

Nature genetics 20211005 10

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 ...[more]

PMID: 34611364

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Project description:Background/objectivesCentral adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of body mass index (BMI) and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition.Subjects/methodsTo identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine-mapping cardiovascular-associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants.ResultsOf the 17 WHR loci, eight single-nucleotide polymorphisms (SNPs) located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine-mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female-stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses.ConclusionsOf 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci.

Project description:Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: <ul><li>A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru</li> <li>A population sample of Easter Island (Rapa Nui), Chile</li> <li>Individuals of indigenous origin from Oaxaca, Mexico</li> <li>Individuals of indigenous origin from Honduras</li> <li>Individuals of indigenous origin from Colombia</li> <li>Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa</li></ul> In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (<a href="https://bustamantelab.stanford.edu/">https://bustamantelab.stanford.edu/</a>). These comprise large public datasets to provide an open reference dataset for the world: <ul><li>The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas</li> <li>A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell</li></ul> Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (<a href="./study.cgi?study_id=phs000356">phs000356</a>).

Dataset Information

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

Publications

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

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