Multiancestral polygenic risk score for pediatric asthma

Abstract

Background: Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.

Objectives: This study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.

Methods: This study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.

Results: The multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, P_FDR = 3.71 × 10^-65) and related phenotypes.

Conclusions: A multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.

Keywords: GWAS; Genetics; PRS; PheWAS; asthma; polygenic risk score.

Figure 1. Study Design.

(A) Summary statistics from 985,837 genetic variants with minor allele frequencies (MAF) greater than 1% in the overall (cases and controls combined) Trans-National Asthma Genetic Consortium (TAGC) Discovery genome-wide association studies (GWAS) were used to develop the multiancestral asthma PRS in the context of the linkage disequilibrium of the reference 1000 genomes reference panel and the Training dataset. (B) The eMERGE dataset was split into two independent datasets (Training and Validation 1) and the UK Biobank was used as a Validation 2 dataset. Subjects with confirmed pediatric-onset asthma and controls were used for PRS Training, Validation 1, and Validation 2. C) Individual genotypes from each subject in each dataset was used to perform a principal component analysis (PCA). For each individual, genotypes at each of the 985,837 variants included in the multiancestral asthma PRS were used to calculate a PCA-adjusted PRS. The adjusted multiancestral PRS was applied to each individual in the Training, Validation 1, and Validation 2 cohorts in preparation for it to be similarly applied to individuals recruited into an IRB-approved prospective intervention study. Figure created in BioRender.

Figure 2.. Multiancestral polygenic risk score (PRS) performance.

Overall adjusted PRS performance are shown for the Training pediatric cohort (A), Validation 1 pediatric cohort (B), and the Validation 2 pediatric cohort (C). The area under the curve (AUC) and 95% percentile of the confidence interval, are shown adjusted for age, sex and 10 ancestral principal components.

Figure 3.. PRS percentile comparison between pediatric patients with asthma and controls.

The violin plots of the median ancestry standardized PRS distributions between cases and controls in pediatric Training (A), Validation 1 (B), and Validation 2 cohorts. In the boxplot insert, the dot within each box indicates the median score. In the Training cohort (A), the median standardized score of cases was 60% vs 47% in controls (p<0.0001). In the Validation 1 cohort (B), the median standardized score of cases was 58% vs 48% in controls (p<0.0001). In the Validation 2 cohort (C), 67% in cases versus 49% in controls (p<0.0001). The top and bottom of the boxes indicate the interquartile range (75th and 25th percentiles), respectively.

Figure 4.. A plot of PheWAS analysis of the asthma PRS within the combined Training and Validation cohorts.

Manhattan plots of phenome-wide association analyses with phecodes (X-axis) and FDR-corrected PheMap phenotype probability (y-axis). The red line indicates the Bonferroni level of significance (5.0 × 10⁻⁵).