In:
Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-10-23)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-020-17315-0
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2553671-0
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