A rare missense variant in NR1H4 associates with lower cholesterol levels

Aimee M. Deaton, Patrick Sulem*, Paul Nioi, Stefania Benonisdottir, Lucas D. Ward, Olafur B. Davidsson, Socheata Lao, Anna Helgadottir, Fan Fan, Brynjar O. Jensson, Gudmundur L. Norddahl, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Asgeir Sigurdsson, Ragnar P. Kristjansson, Asmundur Oddsson, Gudny A. Arnadottir, Hakon Jonsson, Isleifur Olafsson, Gudmundur I. EyjolfssonOlof Sigurdardottir, Einar S. Bjornsson, Sigurdur Olafsson, Thora Steingrimsdottir, Thorunn Rafnar, Gudmundur Thorgeirsson, Gisli Masson, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Hilma Holm, Unnur Thorsteinsdottir, Kari Stefansson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article number14
JournalCommunications Biology
Issue number1
Publication statusPublished - 1 Dec 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).


Dive into the research topics of 'A rare missense variant in NR1H4 associates with lower cholesterol levels'. Together they form a unique fingerprint.

Cite this