Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism

Abstract

Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways.

Fig. 1. Miami plot of the neonatal and maternal GWAS of neonatal jaundice and associations at UGT1A* gene region.

A Miami plot of the GWAS on neonatal jaundice using the neonatal (top, n = 27,384 neonates, cases = 1826) and maternal (bottom, n = 29,182, n cases = 2401) genomes. Genome-wide significant loci are named by their nearest protein coding gene or gene family. The x-axis shows the chromosome position and the y-axis the two-sided p value of the GWAS. The dashed line represents the genome-wide significance threshold (p value = 5 × 10⁻⁸). The bar plot shows the risk of neonatal jaundice by rs6755571 genotype, a missense variant affecting UGT1A4. Error bars in the bar plot represent the 95% CI of the estimate. B A regional plot of the genetic associations with UGT1A1 expression in the colon and liver and with neonatal jaundice at the UGT1A* genes region. Y-axis shows the two-sided p value of the eQTL associations between the variants and UGT1A1 expression in colon or liver (from the eQTL Catalog) and neonatal jaundice (from this study, neonatal genome, n = 27,384, cases = 1826). Highlighted are the missense variant (rs6755571, diamond) and variants in LD with it. LD was estimated in 23,196 non-related neonates from MoBa.

Fig. 2. Effects of the parental transmitted and non-transmitted alleles of the ABO gene variant (rs687621) on neonatal jaundice before or after adjusting for maternal–fetal ABO blood group incompatibility.

Estimates were obtained from a logistic regression model in 23,196 parent–offspring (cases = 1569) with or without a covariate for genetically determined maternal–fetal ABO blood group incompatibility. The dot represents the odds ratio for the association, and the error bars the 95% CI.

Fig. 3. Neonatal jaundice effects of adult bilirubin level variants and polygenic score.

A Genetic effects of the variants at the UGT1A* genes region. Y-axis shows the two-sided p value of the associations between the variants and adult bilirubin levels (a previous publication) or neonatal jaundice (from this study, neonatal genome, n = 27,384, cases = 1826). Highlighted are the top adult variant (rs887829, diamond) and variants in LD with it. LD was estimated in 23,196 non-related mothers from MoBa. B Jaundice prevalence by polygenic score of adult bilirubin levels, including or excluding the UGT1A* genes region, observed in 23,196 neonates (cases = 1569). Weights for the polygenic score of adult bilirubin levels were obtained from the PGS Catalog (ID: PGS002160). Dots represent the neonatal jaundice prevalence, and the error bars the 95% CI.