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.

Figure 1:. Manhattan Plot of Cross-ancestry GWAS of Need for Pharmacotherapy for NAS.

Genome-wide variant associations with need for pharmacotherapy for NAS were calculated separately for AA (N=94) and EA (N=382), adjusting for sex and genetic principal components as covariates. Association testing results for AA and EA neonates were combined via inverse variance-weighted meta-analysis with genomic control. Results were filtered to eliminate variants with MAF < 0.01 and imputation quality < 0.8. One locus on chromosome 7 downstream of SNX13 achieved genome-wide significance.