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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.

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