Effect of bilirubin and Gilbert syndrome on health: cohort analysis of observational, genetic, and Mendelian randomisation associations

OBJECTIVES: To compare associations between the Gilbert syndrome genotype in European populations, measured bilirubin concentrations, genetically predicted bilirubin using this genotype, and a wide range of health outcomes in a large cohort. DESIGN: Cohort study including observational, genetic, and Mendelian randomisation analyses. SETTING: 22 centres across England, Scotland, and Wales in UK Biobank (2006-10), with replication in a national Finnish cohort (FinnGen). PARTICIPANTS: 463 060 participants in the UK Biobank were successfully genotyped for a genetic variant (rs887829) that is strongly associated with Gilbert syndrome and 438 056 participants had measured bilirubin concentrations with linked electronic health record data coded using the tenth edition of the International Classification of Diseases. Replication analyses were performed in FinnGen (n=429 209) with linked electronic health record data. MAIN OUTCOME MEASURES: Odds ratios for the association between serum bilirubin concentrations, rs887829-T homozygosity (the risk genotype for Gilbert syndrome), genetically predicted bilirubin using rs887829-T allele carriage alone, and a wide range of health outcomes recorded in primary and secondary care. RESULTS: 46 189 participants in UK Biobank (about 10%) were homozygous for rs887829-T defining them as having the genotype characterising Gilbert syndrome. However, only 1701 (3%) of this group had a coded diagnosis of Gilbert syndrome. Variation at this locus explained 37.1% of all variation in measured serum bilirubin. In the observational analyses, higher bilirubin concentrations had strong inverse associations with a wide range of outcomes including overall health status, chronic obstructive pulmonary disease, myocardial infarction, and cholesterol measures. These associations were not identified in people with the Gilbert genotype. We identified associations with genetically predicted bilirubin concentrations and biliary and liver pathology (eg, odds ratio for cholelithiasis 1.16 (95% confidence interval 1.12 to 1.20); P=5.7×10(-16)) and a novel association with pityriasis rosea (1.47 (1.27 to 1.69), P=1.28×10(-7)). CONCLUSIONS: Only 3% of participants who are homozygous for rs887829-T have a recorded diagnosis of Gilbert syndrome. Carriers of this genotype have modest increases in the odds of developing biliary pathology and pityriasis rosea. Evidence from the analyses of genetic data suggests that bilirubin has no likely causal role in protection from cardiovascular disease, chronic obstructive pulmonary disease, or other key healthcare outcomes and therefore represents a poor target for therapeutic intervention for these outcomes.