MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk

Ida Surakka, Lars G. Fritsche, Wei Zhou, Joshua Backman, Jack A. Kosmicki, Haocheng Lu, Ben Brumpton, Jonas B. Nielsen, Maiken E. Gabrielsen, Anne Heidi Skogholt, Brooke Wolford, Sarah E. Graham, Y. Eugene Chen, Seunggeun Lee, Hyun Min Kang, Arnulf Langhammer, Siri Forsmo, Bjørn O. Åsvold, Unnur Styrkarsdottir, Hilma Holm, Daniel Gudbjartsson, Kari Stefansson, Aris Baras, Goncalo R. Abecasis, Kristian Hveem () and Cristen J. Willer ()
Additional contact information
Ida Surakka: University of Michigan
Lars G. Fritsche: University of Michigan
Wei Zhou: Broad Institute of Harvard and MIT
Joshua Backman: Regeneron Genetics Center
Jack A. Kosmicki: Regeneron Genetics Center
Haocheng Lu: University of Michigan
Ben Brumpton: Norwegian University of Science and Technology
Jonas B. Nielsen: University of Michigan
Maiken E. Gabrielsen: Norwegian University of Science and Technology
Anne Heidi Skogholt: Norwegian University of Science and Technology
Brooke Wolford: University of Michigan, Palmer Commons
Sarah E. Graham: University of Michigan
Y. Eugene Chen: University of Michigan
Seunggeun Lee: University of Michigan School of Public Health
Hyun Min Kang: University of Michigan School of Public Health
Arnulf Langhammer: Norwegian University of Science and Technology
Siri Forsmo: Norwegian University of Science and Technology
Bjørn O. Åsvold: Norwegian University of Science and Technology
Unnur Styrkarsdottir: deCODE genetics/Amgen, Inc.
Hilma Holm: deCODE genetics/Amgen, Inc.
Daniel Gudbjartsson: deCODE genetics/Amgen, Inc.
Kari Stefansson: deCODE genetics/Amgen, Inc.
Aris Baras: Regeneron Genetics Center
Goncalo R. Abecasis: University of Michigan School of Public Health
Kristian Hveem: Norwegian University of Science and Technology
Cristen J. Willer: University of Michigan

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: Abstract A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. We searched for variants associated with bone mineral density (BMD) after enriching the discovery cohort for loss-of-function (LoF) mutations by sequencing a subset of the Nord-Trøndelag Health Study, followed by imputation in the remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation in MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] = 0.8%), was associated with decreased ultradistal forearm BMD (P-value = 2.1 × 10−18), and increased osteoporosis (P-value = 4.2 × 10−5) and fracture risk (P-value = 1.6 × 10−5). The MEPE LoF association with BMD and fractures was further evaluated in 279,435 UK (MAF = 0.05%, heel bone estimated BMD P-value = 1.2 × 10−16, any fracture P-value = 0.05) and 375,984 Icelandic samples (MAF = 0.03%, arm BMD P-value = 0.12, forearm fracture P-value = 0.005). Screening for the MEPE LoF mutations before adulthood could potentially prevent osteoporosis and fractures due to the lifelong effect on BMD observed in the study. A key implication for precision medicine is that high-impact functional variants missing from the publicly available cosmopolitan panels could be clinically more relevant than polygenic risk scores.

Date: 2020
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DOI: 10.1038/s41467-020-17315-0

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