Shawana Bibi1, Nathan Gaddis2, Eric O Johnson2, Barry M Lester3, Walter Kraft4, Rachana Singh1, Norma Terrin5, Susan Adeniyi-Jones6, Jonathan M Davis7,8. 1. Division of Newborn Medicine, Tufts Medical Center, Boston, MA, USA. 2. RTI International, Research Triangle Park, NC, USA. 3. Department of Pediatrics, Alpert Medical School of Brown University and Women and Infants Hospital, Providence, RI, USA. 4. Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA, USA. 5. Tufts Clinical and Translational Science Institute, Tufts School of Graduate Biomedical Sciences, Boston, MA, USA. 6. Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA. 7. Division of Newborn Medicine, Tufts Medical Center, Boston, MA, USA. jdavis@tuftsmedicalcenter.org. 8. Tufts Clinical and Translational Science Institute, Tufts School of Graduate Biomedical Sciences, Boston, MA, USA. jdavis@tuftsmedicalcenter.org.
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.
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.
Authors: Tyler N A Winkelman; Nicole Villapiano; Katy B Kozhimannil; Matthew M Davis; Stephen W Patrick Journal: Pediatrics Date: 2018-04 Impact factor: 7.124
Authors: Stephen W Patrick; James C Slaughter; Frank E Harrell; Peter R Martin; Katherine Hartmann; Judith Dudley; Shannon Stratton; William O Cooper Journal: J Pediatr Date: 2020-10-17 Impact factor: 4.406