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

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 ≈ 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. 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. B.J. received funding from The Swedish Research Council, Stockholm, Sweden (2019-01004), The Research Council of Norway, Oslo, Norway (FRIMEDBIO #547711), March of Dimes (#21-FY16-121), Agreement concerning research and education of doctors (ALFGBG-965353). This study was in part supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. G.Z. is supported by the Burroughs Wellcome Fund (Grant 10172896), and the March of Dimes Prematurity Research Center Ohio Collaborative. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All study participants provided a signed informed consent, and the study protocol has been approved by the administrative board of the Norwegian Mother, Father and Child Cohort Study, led by the Norwegian Institute of Public Health. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committee for Medical Research Ethics. The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics South-East (2015/2425) and by the Swedish Ethical Review Authority (Dnr 2022-03248-01). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. 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