Multiancestral polygenic risk score for pediatric asthma - 03/11/22
The eMERGE Networkw
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, PFDR = 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.
Le texte complet de cet article est disponible en PDF.Key words : Genetics, asthma, GWAS, polygenic risk score, PRS, PheWAS
Abbreviations used : AUC, eMERGE, FDR, GWAS, ICD, LD, OR, PCA, PheWAS, PRS, TAGC
Plan
| Supported by grants NIH R01 HG010730, NIH R01 NS099068, NIH R01 GM055479, NIH U01 AI130830, NIH R01 AI141569, and NIH U01 AI150748 to M.T.W.; grants NIH R01 DK107502, NIH R01 AI148276, NIH U19 AI070235, NIH U01 HG011172, and NIH P30 AR070549 to L.C.K.; grants NIH R01 AR073228 and NIH R01 AI024717 and Cincinnati Children’s Hospital Medical Center Academic Research Committee (ARC) Award 53632 to M.T.W. and L.C.K.; grants NIH R01 HG010166, NIH R01 HL145422, NIH R25 GM129808, NIH R01 AI127392, NIH UG3 OD023282, NIH U19 AI070235, NIH U54 AI117804, NIH R01 NS096053, NIH R01 DK107502, NIH R01 HD089458, NIH R01 HL132153, NIH R01 AI139126, NIH R01 HL135114, NIH R01 HD099775, and NIH U01 HG011172 to L.J.M.; and grants NIH R01 HL132344 and NIH R01 HG011411 to T.B.M. |
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| The eMERGE (Electronic Medical Records and Genomics) Network was initiated and funded by the National Human Genome Research Institute through the following grants: Phase IV: U01 HG011172 to Cincinnati Children’s Hospital Medical Center; U01 HG011175 to Children’s Hospital of Philadelphia; U01 HG008680 to Columbia University; U01 HG011176 to Icahn School of Medicine at Mount Sinai; U01 HG008685 to Mass General Brigham; U01 HG006379 to Mayo Clinic; U01 HG011169 to Northwestern University; U01 HG011167 to University of Alabama at Birmingham; U01 HG008657 to University of Washington; U01 HG011181 to Vanderbilt University Medical Center; U01 HG011166 to Vanderbilt University Medical Center serving as the Coordinating Center. Phase III: U01 HG8657 to Kaiser Permanente Washington/University of Washington; U01 HG8685 to Brigham and Women’s Hospital; U01 HG8672 to Vanderbilt University Medical Center; U01 HG8666 to Cincinnati Children’s Hospital Medical Center; U01 HG6379 to Mayo Clinic; U01 HG8679 to Geisinger Clinic; U01 HG8680 to Columbia University Health Sciences; U01 HG8684 to Children’s Hospital of Philadelphia; U01 HG8673 to Northwestern University; U01 HG8701 to Vanderbilt University Medical Center serving as the Coordinating Center; U01 HG8676 to Partners Healthcare/Broad Institute; and U01 HG8664 to Baylor College of Medicine. Phase II: U01 HG006828 to Cincinnati Children’s Hospital Medical Center/Boston Children’s Hospital; U01 HG006830 to Children’s Hospital of Philadelphia; U01 HG006389 to Essentia Institute of Rural Health, Marshfield Clinic Research Foundation, and Pennsylvania State University; U01 HG006382 to Geisinger Clinic; U01 HG006375 to Group Health Cooperative/University of Washington; U01 HG006379 to Mayo Clinic; U01 HG006380 to Icahn School of Medicine at Mount Sinai; U01 HG006388 to Northwestern University; U01 HG006378 to Vanderbilt University Medical Center; and U01 HG006385 to Vanderbilt University Medical Center serving as the Coordinating Center. Genotyping center support U01 HG004438 to Center for Inherited Disease Research and U01 HG004424 to the Broad Institute. Phase I: U01 HG004610 to Group Health Cooperative/University of Washington; U01 HG004608 to Marshfield Clinic Research Foundation and Vanderbilt University Medical Center; U01 HG04599 to Mayo Clinic; U01 HG004609 to Northwestern University; U01 HG04603 to Vanderbilt University Medical Center, also serving as the Administrative Coordinating Center; U01 HG004438 to Center for Inherited Disease Research; and U01 HG004424 to the Broad Institute serving as genotyping centers. |
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| This research has been conducted using data from UK Biobank, a major biomedical database (www.ukbiobank.ac.uk/). |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 150 - N° 5
P. 1086-1096 - novembre 2022 Retour au numéro
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