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dc.contributor.authorSurakka, Ida
dc.contributor.authorFritsche, Lars
dc.contributor.authorZhou, Wei
dc.contributor.authorBackman, Joshua
dc.contributor.authorKosmicki, Jack A.
dc.contributor.authorLu, Haocheng
dc.contributor.authorBrumpton, Ben Michael
dc.contributor.authorNielsen, Jonas B.
dc.contributor.authorGabrielsen, Maiken Elvestad
dc.contributor.authorSkogholt, Anne Heidi
dc.contributor.authorWolford, Brooke N.
dc.contributor.authorGraham, Sarah E.
dc.contributor.authorChen, Y. Eugene
dc.contributor.authorLee, Seunggeun
dc.contributor.authorKang, Hyun Min
dc.contributor.authorLanghammer, Arnulf
dc.contributor.authorForsmo, Siri
dc.contributor.authorÅsvold, Bjørn Olav
dc.contributor.authorStyrkarsdottir, Unnur
dc.contributor.authorHolm, Hilma
dc.contributor.authorGudbjartsson, Daniel F.
dc.contributor.authorStefansson, Kari
dc.contributor.authorBaras, Aris
dc.contributor.authorBai, Xiaodong
dc.contributor.authorBalasubramanian, Suganthi
dc.contributor.authorBarnard, Leland
dc.contributor.authorBlumenfeld, Andrew
dc.contributor.authorCantor, Michael
dc.contributor.authorCoppola, Giovanni
dc.contributor.authorEconomides, Aris
dc.contributor.authorEom, Gisu
dc.contributor.authorHabegger, Lukas
dc.contributor.authorHahn, Young
dc.contributor.authorHawes, Alicia
dc.contributor.authorJones, Marcus B.
dc.contributor.authorKhalid, Shareef
dc.contributor.authorLotta, Luca A.
dc.contributor.authorMaxwell, Evan K.
dc.contributor.authorMitnaul, Lyndon J.
dc.contributor.authorOverton, John D.
dc.contributor.authorReid, Jeffrey G.
dc.contributor.authorFerreira, Manuel Allen Revez
dc.contributor.authorSalerno, William
dc.contributor.authorSharma, Deepika
dc.contributor.authorShuldiner, Alan R.
dc.contributor.authorStaples, Jeffrey C.
dc.contributor.authorYadav, Ashish
dc.contributor.authorAbecasis, Goncalo R.
dc.contributor.authorHveem, Kristian
dc.contributor.authorWiller, Cristen J.
dc.identifier.citationNature Communications. 2020, 11:4093 1-8.en_US
dc.description.abstractA 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.en_US
dc.publisherNature Researchen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleMEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risken_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.source.journalNature Communicationsen_US
dc.relation.projectStiftelsen Kristian Gerhard Jebsen: SKGJ-MED015en_US

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Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal