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

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-TrOndelag 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 = 2.1x10(-18)), and increased osteoporosis (P-value = 4.2x10(-5)) and fracture risk (P-value = 1.6x10(-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 = 1.2x10(-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. Bone mineral density (BMD) is associated with fracture risk and many genetic loci with small effect sizes have been discovered by genome-wide association studies (GWAS). Here, the authors discover a large-effect rare loss-of-function genetic variant for BMD in the MEPE gene in the Norwegian HUNT study which replicates in the UK Biobank.