A rare missense variant in 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 (R436H) associating with lower levels of total cholesterol (effect = -0.47 standard deviations or -0.55 mmol L,  = 4.21 × 10,  = 150,211). Importantly, R436H also associates with lower levels of non-HDL cholesterol and, consistent with this, protects against coronary artery disease. 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.