MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk
| Autor: | Surakka, Ida, Fritsche, Lars, Zhou, Wei, Backman, Joshua, Kosmicki, Jack A., Lu, Haocheng, Brumpton, Ben Michael, Nielsen, Jonas B., Gabrielsen, Maiken Elvestad, Skogholt, Anne Heidi, Wolford, Brooke N., Graham, Sarah E., Chen, Y. Eugene, Lee, Seunggeun, Kang, Hyun Min, Langhammer, Arnulf, Forsmo, Siri, Åsvold, Bjørn Olav, Styrkarsdottir, Unnur, Holm, Hilma, Gudbjartsson, Daniel F., Stefansson, Kari, Baras, Aris, Bai, Xiaodong, Balasubramanian, Suganthi, Barnard, Leland, Blumenfeld, Andrew, Cantor, Michael, Coppola, Giovanni, Economides, Aris, Eom, Gisu, Habegger, Lukas, Hahn, Young, Hawes, Alicia, Jones, Marcus B., Khalid, Shareef, Lotta, Luca A., Maxwell, Evan K., Mitnaul, Lyndon J., Overton, John D., Reid, Jeffrey G., Ferreira, Manuel Allen Revez, Salerno, William, Sharma, Deepika, Shuldiner, Alan R., Staples, Jeffrey C., Yadav, Ashish, Abecasis, Goncalo R., Hveem, Kristian, Willer, Cristen J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Male Osteoporosis Iceland General Physics and Astronomy Genome-wide association study Genome-wide association studies Cohort Studies Fractures Bone 0302 clinical medicine Gene Frequency Bone Density lcsh:Science Bone mineral Aged 80 and over Extracellular Matrix Proteins Multidisciplinary Middle Aged Cohort Female musculoskeletal diseases Adult medicine.medical_specialty Science Predictive medicine 030209 endocrinology & metabolism General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Internal medicine medicine Genetics Humans Genetic Predisposition to Disease Genetic Testing Genetic Association Studies Genetic association Genetic association study Aged Glycoproteins business.industry Genome Human Computational Biology General Chemistry medicine.disease Phosphoproteins Computational biology and bioinformatics Minor allele frequency 030104 developmental biology MEPE lcsh:Q business Imputation (genetics) |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-8 (2020) 11:4093 |
| ISSN: | 2041-1723 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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