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

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.

Fig. 1. Ultradistal forearm BMD Genome-wide association analysis results.

Manhattan (upper panel) and QQ-plot (lower panel) in HUNT dataset (N = 19,705) for ultradistal forearm bone mineral density (BMD) genome-wide association analysis. In the Manhattan plot (upper panel) the genome-wide significance threshold (P-value < 5 × 10⁻⁸) is shown using a red dotted line. In the QQ-plot (lower panel), the tested variants have been divided into four groups based on MAF (red dots = MAF [0.05; 0.5], blue dots = MAF [0.005; 0.05], green dots = MAF [0.001; 0.005], purple dots = MAF [0.000253; 0.001]). MAF: minor allele frequency. −log₁₀P: −1 × tenth logarithm of the association test P-value.

Fig. 2. Age trend in BMD for MEPE LoF mutation carriers.

In this figure we have compared the forearm bone mineral density (BMD) in the MEPE loss-of-function (LoF) mutation, p.Lys70IlefsTer26, carriers (dotted lines) compared to non-carriers (solid lines) in the HUNT dataset (N = 19,705). The trend over different ages is illustrated using LOWESS curve for males (blue lines) and females (red lines) separately.