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

Published on Oct 1, 2021in Nature Genetics38.33
· DOI :10.1038/S41588-021-00935-7
Yang Luo17
Estimated H-index: 17
Masahiro Kanai27
Estimated H-index: 27
+ 429 AuthorsPhilip E. Stuart42
Estimated H-index: 42
(UM: University of Michigan)
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. A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of HLA alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.
#189Timothy D. O’Connor (UMB: University of Maryland, Baltimore)H-Index: 20
#190Gonçalo R. Abecasis (UM: University of Michigan)H-Index: 180
The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from th...
#1Emily T. Norris (Georgia Institute of Technology)H-Index: 8
#2Lavanya Rishishwar (Georgia Institute of Technology)H-Index: 18
Last. I. King Jordan (Georgia Institute of Technology)H-Index: 46
view all 7 authors...
BACKGROUND: Admixture occurs when previously isolated populations come together and exchange genetic material. We hypothesize that admixture can enable rapid adaptive evolution in human populations by introducing novel genetic variants (haplotypes) at intermediate frequencies, and we test this hypothesis through the analysis of whole genome sequences sampled from admixed Latin American populations in Colombia, Mexico, Peru, and Puerto Rico. RESULTS: Our screen for admixture-enabled selection rel...
#1Faviel F. Gonzalez-Galarza (Autonomous University of Coahuila)H-Index: 16
#2Antony McCabe (University of Liverpool)H-Index: 6
Last. Andrew R. Jones (University of Liverpool)H-Index: 36
view all 12 authors...
Abstract The Allele Frequency Net Database (AFND, www.allelefrequencies.net) provides the scientific community with a freely available repository for the storage of frequency data (alleles, genes, haplotypes and genotypes) related to human leukocyte antigens (HLA), killer-cell immunoglobulin-like receptors (KIR), major histocompatibility complex Class I chain related genes (MIC) and a number of cytokine gene polymorphisms in worldwide populations. In the last five years, AFND has become more pop...
#1James Robinson (UCL: University College London)H-Index: 59
#2Dominic J. Barker (Anthony Nolan)H-Index: 2
Last. Steven G.E. Marsh (UCL: University College London)H-Index: 72
view all 6 authors...
The IPD-IMGT/HLA Database, http://www.ebi.ac.uk/ipd/imgt/hla/, currently contains over 25 000 allele sequence for 45 genes, which are located within the Major Histocompatibility Complex (MHC) of the human genome. This region is the most polymorphic region of the human genome, and the levels of polymorphism seen exceed most other genes. Some of the genes have several thousand variants and are now termed hyperpolymorphic, rather than just simply polymorphic. The IPD-IMGT/HLA Database has provided ...
#1Michael Salter-Townshend (UCD: University College Dublin)H-Index: 10
#2Simon Myers (Wellcome Trust Centre for Human Genetics)H-Index: 59
We present an algorithm for inferring ancestry segments and characterizing admixture events, which involve an arbitrary number of genetically differentiated groups coming together. This allows inference of the demographic history of the species, properties of admixing groups, identification of signatures of natural selection, and may aid disease gene mapping. The algorithm employs nested hidden Markov models to obtain local ancestry estimation along the genome for each admixed individual. In a r...
#1Frauke Degenhardt (CAU: University of Kiel)H-Index: 16
#2Mareike Wendorff (CAU: University of Kiel)H-Index: 6
Last. Andre Franke (CAU: University of Kiel)H-Index: 124
view all 28 authors...
Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genot...
#1Gaurav D. Gaiha (Harvard University)H-Index: 10
#2Elizabeth J. Rossin (Broad Institute)H-Index: 21
Last. Bruce D. WalkerH-Index: 171
view all 18 authors...
Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes ...
#1Ali Torkamani (Scripps Health)H-Index: 47
#2Eric J. Topol (Scripps Health)H-Index: 224
Obesity is one of the most serious health challenges of our time. In this issue of Cell, Khera and co-authors demonstrate the striking ability of genetics, in the form of a polygenic risk score, to identify those individuals at high risk for obesity. This genetic risk expresses itself early as childhood obesity, reinforcing the notion that early prevention is essential to combatting the obesity epidemic.
#1Amit KheraH-Index: 76
#2Mark Chaffin (Broad Institute)H-Index: 28
Last. Sekar KathiresanH-Index: 141
view all 19 authors...
Summary Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals rangin...
#1Alexander T. Dilthey (University of Oxford)H-Index: 29
#2Alexander J. Mentzer (University of Oxford)H-Index: 31
Last. Adam M. Phillippy (NIH: National Institutes of Health)H-Index: 61
view all 11 authors...
SUMMARY: HLA*LA implements a new graph alignment model for human leukocyte antigen (HLA) type inference, based on the projection of linear alignments onto a variation graph. It enables accurate HLA type inference from whole-genome (99% accuracy) and whole-exome (93% accuracy) Illumina data; from long-read Oxford Nanopore and Pacific Biosciences data (98% accuracy for whole-genome and targeted data) and from genome assemblies. Computational requirements for a typical sample vary between 0.7 and 1...
Cited By0
#1Tatsuhiko Naito (Osaka University)H-Index: 5
#2Yukinori Okada (Osaka University)H-Index: 70
Variations of human leukocyte antigen (HLA) genes in the major histocompatibility complex region (MHC) significantly affect the risk of various diseases, especially autoimmune diseases. Fine-mapping of causal variants in this region was challenging due to the difficulty in sequencing and its inapplicability to large cohorts. Thus, HLA imputation, a method to infer HLA types from regional single nucleotide polymorphisms, has been developed and has successfully contributed to MHC fine-mapping of v...
This website uses cookies.
We use cookies to improve your online experience. By continuing to use our website we assume you agree to the placement of these cookies.
To learn more, you can find in our Privacy Policy.