| Title: | MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk |
| Journal: | Nature Communications |
| Published: | 23 Oct 2020 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33097703/ |
| DOI: | https://doi.org/10.1038/s41467-020-17315-0 |
| URL: | https://www.nature.com/articles/s41467-020-17315-0.pdf |
Publication 9269
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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.</p>
26 Authors
- 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
- Cristen J. Willer
Enabling scientific discoveries that improve human health