Division of Newborn Medicine, Tufts Medical Center, Boston, MA, USA.
RTI International, Research Triangle Park, NC, USA.
Pediatr Res. 2023 Apr;93(5):1368-1374. doi: 10.1038/s41390-022-02243-0. Epub 2022 Aug 16.
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.
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.
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.
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.
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.
本研究旨在通过全基因组关联研究（GWAS）鉴定与 NAS 相关的遗传变异，并估计 NAS 的多基因风险评分（PRS）模型。
一项前瞻性病例对照研究纳入了 476 例宫内暴露于阿片类药物的足月新生儿。对 1000 个基因组进行基因型推断，以鉴定与 NAS 需要药物治疗相关的变异。使用 382 名欧洲血统的新生儿通过嵌套交叉验证方法生成用于估计遗传易感性的 PRS 模型。评估 PRS 的预测能力、区分度和校准。
跨血统 GWAS 在染色体 7 上 SNX13 下游的一个基因间区域鉴定出与需要药物治疗的相关性具有全基因组关联。从欧洲血统新生儿的 GWAS 中得出的 PRS 模型可以可靠地区分欧洲和非裔美国血统新生儿验证集中需要药物治疗的情况，使用 cis 变体效应大小。当在跨数据集和校准分析中应用变体效应大小时，PRS 的效果较差。
GWAS 有可能鉴定与 NAS 药物治疗需求相关的遗传位点，并能够开发具有临床预测性的 PRS 模型。需要更大的具有其他血统的 GWAS 来确认观察到的 SNX13 关联和 PRS 在 NAS 风险预测模型中的准确性。
遗传关联似乎在新生儿戒断综合征中很重要。这是首例对患有新生儿戒断综合征的新生儿进行的全基因组关联研究。多基因风险评分可以通过检查整个基因组中的单核苷酸多态性来开发。接受药物治疗治疗新生儿戒断综合征的新生儿的多基因风险评分较高。需要更大的队列研究来更好地阐明这些遗传关联。
