An epidemic of neonatal abstinence syndrome (NAS) currently exists due to dramatic increases in prenatal opioid exposure. Significant variability has been observed in the development and severity of NAS among neonates exposed to prenatal opioids. This suggests that genetic factors may be playing a significant role. This has prompted case control studies that have examined the association of several single nucleotide polymorphisms (SNPs) in genes known to be involved in opioid metabolism and addiction with length of hospitalization, need for pharmacologic treatment, and total days of opioid treatment in neonates with NAS (1). Previous studies in small cohorts have demonstrated an association with genetic variants in the OPRM1, COMT, and PNOC genes with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero (2,3).
We recently conducted a multisite randomized controlled trial examining the most common pharmacologic treatments in infants with NAS. If parents refused the treatment portion, they could still consent to data collection and buccal swabs for genomic analyses in infants. A total of 262 infants had adequate samples and data available. Isolated DNA was tested on the Illumina Omni Array with 2.5 million SNPs involving addiction, psychiatric diseases, opioid metabolism. Once we filtered out markers defying Hardy Weinberg equilibrium or those unable to be precisely mapped, 1.3 million markers remained for testing. While 24,000 SNPs met genome-wide significance at p<0.05 with false discovery rates of 5%, 29 SNPs met significance using 1%, and 9 SNPs met significance using a cutoff of 5x10-5. While analysis of individual SNPs was important, a focus on biologic plausibility through pathway analysis was considered to be more robust. KEGG and PANTHER pathway analyses found genes involved with drug detoxification, inflammation, and antioxidant capacity to be associated with the development and severity of NAS. Genes associated with GABAnergic synapses, morphine and nicotine addiction, endocannabinoid signaling, opioid proenkephalin pathways, enkephalin release, and histamine signaling and release were also found to have important associations. Preliminary data indicate that genetic factors are associated with NAS. However, larger scale trials with a nationwide biobank will be needed to establish more definitive associations in order to implement a more targeted and Precision Medicine approach to NAS.
1. Lewis T, Dinh J, Leeder JS. Genetic determinants of fetal opiate exposure and risk of neonatal abstinence syndrome: Knowledge deficits and prospects for future research. Clin Pharm Ther. 2015;98:309-20.
2. Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, et al. Association of OPRM1 and COMT single-nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA. 2013;309:1821-7.
3. Wachman EM, Hayes MJ, Sherva R, Brown MS, Davis JM, Farrer LA, et al. Variations in opioid receptor genes in neonatal abstinence syndrome. Drug Alcohol Depend. 2015;155:253-9.
Gene Finding Strategies , Substance use: Alcohol, Nicotine, Drugs
