Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.
Max HomiliusWandi ZhuSamuel S EddyPatrick C ThompsonHuahua ZhengCaleb N WarrenChiara G EvansDavid D KimLucius L XuanCissy NsubugaZachary StreckerChristopher J PettitJungwoo ChoMikayla N HowieAlexandra S ThalerEvan WilsonBruce WollisonCourtney SmithJulia B NascimbenDiana N NascimbenGabriella M LunatiHassan C FolksMatthew CupeloSuriya SridaranCarolyn RheinsteinTaylor McClennenShinichi GotoJames G TruslowSara VandenwijngaertCalum A MacRaeRahul C DeoPublished in: Nature genetics (2023)
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.
Keyphrases
- genome wide
- end stage renal disease
- chronic kidney disease
- peripheral blood
- endothelial cells
- type diabetes
- copy number
- peritoneal dialysis
- induced apoptosis
- genome wide association
- newly diagnosed
- flow cytometry
- dna methylation
- induced pluripotent stem cells
- gene expression
- mental health
- cell cycle arrest
- pluripotent stem cells
- patient reported outcomes
- high throughput
- single cell
- oxidative stress
- endoplasmic reticulum stress
- insulin resistance
- genome wide association study
- glycemic control