A rare missense variant in NR1H4 associates with lower cholesterol levels

Searching for novel sequence variants associated with cholesterol levels is of particular interest due to the causative role of non-HDL cholesterol levels in cardiovascular disease. Through whole-genome sequencing of 15,220 Icelanders and imputation of the variants identified, we discovered a rare missense variant in NR1H4 (R436H) associating with lower levels of total cholesterol (effect = −0.47 standard deviations or −0.55 mmol L −1 , p = 4.21 × 10 −10 , N = 150,211). Importantly, NR1H4 R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. NR1H4 encodes FXR that regulates bile acid homeostasis, however, we do not detect a significant association between R436H and biological markers of liver function. Transcriptional profiling of hepatocytes carrying R436H shows that it is not a loss-of-function variant. Rather, we observe changes in gene expression compatible with effects on lipids. These findings highlight the role of FXR in regulation of cholesterol levels in humans. Aimee Deaton et al. identify a rare missense variant in the bile acid receptor gene NR1H4 , which is associated with lower levels of total cholesterol in the Icelandic population. Hepatocytes expressing the missense variant showed altered expression of a small number of genes, with enrichment in lipid-related pathways.