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Polygenic risk scores and the need for pharmacotherapy in neonatal abstinence syndrome

Abstract

Background

The aim of this study was to identify genetic variants associated with NAS through a genome-wide association study (GWAS) and estimate a Polygenic Risk Score (PRS) model for NAS.

Methods

A prospective case–control study included 476 in utero opioid-exposed term neonates. A GWAS of 1000 genomes-imputed genotypes was performed to identify variants associated with need for pharmacotherapy for NAS. PRS models for estimating genetic predisposition were generated via a nested cross-validation approach using 382 neonates of European ancestry. PRS predictive ability, discrimination, and calibration were assessed.

Results

Cross-ancestry GWAS identified one intergenic locus on chromosome 7 downstream of SNX13 exhibiting genome-wide association with need for pharmacotherapy. PRS models derived from the GWAS for a subset of the European ancestry neonates reliably discriminated between need for pharmacotherapy using cis variant effect sizes within validation sets of European and African American ancestry neonates. PRS were less effective when applying variant effect sizes across datasets and in calibration analyses.

Conclusions

GWAS has the potential to identify genetic loci associated with need for pharmacotherapy for NAS and enable development of clinically predictive PRS models. Larger GWAS with additional ancestries are needed to confirm the observed SNX13 association and the accuracy of PRS in NAS risk prediction models.

Impact

  • Genetic associations appear to be important in neonatal abstinence syndrome.

  • This is the first genome-wide association in neonates with neonatal abstinence syndrome.

  • Polygenic risk scores can be developed examining single-nucleotide polymorphisms across the entire genome.

  • Polygenic risk scores were higher in neonates receiving pharmacotherapy for treatment of their neonatal abstinence syndrome.

  • Future studies with larger cohorts are needed to better delineate these genetic associations.

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Fig. 1: Manhattan plot of cross-ancestry GWAS of need for pharmacotherapy for NAS.

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Acknowledgements

The authors want to thank: Adam Czynski, Erica Oliveira—Brown, Mark Hudak—Jacksonville, Jeffrey Shenberger—Baystate Medical Center, Peter Marro—Maine Medical Center, Elisha Wachman—Boston Medical Center, Barbara Engelhardt—Vanderbilt, Debra Bogen—University of Pittsburgh, and Michelle Ehrlich—Mt. Sinai.

Funding

This study was funded by the National Institute of Drug Abuse (NIDA) R01DA032889, R21DA041706-02 (to J.M.D., B.M.L.), NIDA R01DA02976 (to W.K.), and Charles H. Hood Foundation (to J.M.D.).

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All authors were involved with the planning, conduct, analyses, interpretation, and writing of the study; W.K., S.A.-J., B.M.L., and J.M.D. were involved in patient recruitment for the study.

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Correspondence to Jonathan M. Davis.

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Bibi, S., Gaddis, N., Johnson, E.O. et al. Polygenic risk scores and the need for pharmacotherapy in neonatal abstinence syndrome. Pediatr Res (2022). https://doi.org/10.1038/s41390-022-02243-0

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