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.
Highlights
A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome
The standard technology in use at that time was single-energy x-ray absorptiometry (SXA), and the decision was made to focus on ultradistal forearm bone mineral density (BMD) measurements
This is not the current standard used in clinic or hospital-based cohort collections, the HUNT study has the advantage of a populationbased screening of individuals with a wide variety of ages, with the inclusion of healthy individuals relative to a clinic-based phenotype, and decades of longitudinal clinical follow-up including fractures
Summary
A major challenge in genetic association studies is that most associated variants fall in the non-coding part of the human genome. To advance the translation of genetic discovery to improved therapeutics and prevention via prediction of at-risk individuals, we sought to identify rare and low-frequency loss-of-function (LoF) variants associated with BMD and fractures through a genome-wide association study (GWAS). We employed methodology wherein we performed low-pass sequencing of a subset of the sample (N = 2202), imputed variants, including insertion/deletion polymorphisms, into the remainder of the HUNT discovery sample (N = 19,705) followed by replication of previously unreported variants in two independent replication samples: UK Biobank (N = 279,435) and deCODE (N = 170,000) Using this approach, we identify a LoF mutation in MEPE, which may be useful for precision medicine and therapeutic development
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