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Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

ABSTRACT: Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.

SUBMITTER: Homilius M

PROVIDER: S-EPMC10786715 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Homilius Max M Zhu Wandi W Eddy Samuel S SS Thompson Patrick C PC Zheng Huahua H Warren Caleb N CN Evans Chiara G CG Kim David D DD Xuan Lucius L LL Nsubuga Cissy C Strecker Zachary Z Pettit Christopher J CJ Cho Jungwoo J Howie Mikayla N MN Thaler Alexandra S AS Wilson Evan E Wollison Bruce B Smith Courtney C Nascimben Julia B JB Nascimben Diana N DN Lunati Gabriella M GM Folks Hassan C HC Cupelo Matthew M Sridaran Suriya S Rheinstein Carolyn C McClennen Taylor T Goto Shinichi S Truslow James G JG Vandenwijngaert Sara S MacRae Calum A CA Deo Rahul C RC

Nature genetics 20231204 1

Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 indivi ...[more]

PMID: 38049662

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Project description:BackgroundPolygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest.MethodsTo select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas.ResultsWe confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components.ConclusionOur work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

Dataset Information

Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Publications

Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

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