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 in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2,000), with the most compelling locus located in the UGT1A* genes region. The alternate allele of a common missense variant affecting the sequence of UGT1A4 (with low affinity for bilirubin) reduces the susceptibility to jaundice five-fold (rs6755571, A allele OR = 0.2, p-value = 2.7 × 10?55, frequency = 6.4%). eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 (the primary bilirubin conjugation enzyme) in the intestines, but not in the liver. The analysis of the parental transmitted and non-transmitted alleles in 23,000 parent-offspring trios captures known effects of maternal-fetal ABO blood group incompatibility on neonatal jaundice. Our results reveal marked differences in the pathways involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting a distinct biological basis.