An atlas of genetic influences on osteoporosis in humans and mice.

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Morris, John A (author)

An atlas of genetic influences on osteoporosis in humans and mice.

Article/chapterEnglish2019

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2018-12-31
Springer Science and Business Media LLC,2019

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LIBRIS-ID:oai:gup.ub.gu.se/276254
https://gup.ub.gu.se/publication/276254URI
https://doi.org/10.1038/s41588-018-0302-xDOI

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Language:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR)=58, P=1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P<0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

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Kemp, John P (author)
Youlten, Scott E (author)
Laurent, Laetitia (author)
Logan, John G (author)
Chai, Ryan C (author)
Vulpescu, Nicholas A (author)
Forgetta, Vincenzo (author)
Kleinman, Aaron (author)
Mohanty, Sindhu T (author)
Sergio, C Marcelo (author)
Quinn, Julian (author)
Nguyen-Yamamoto, Loan (author)
Luco, Aimee-Lee (author)
Vijay, Jinchu (author)
Simon, Marie-Michelle (author)
Pramatarova, Albena (author)
Medina-Gomez, Carolina (author)
Trajanoska, Katerina (author)
Ghirardello, Elena J (author)
Butterfield, Natalie C (author)
Curry, Katharine F (author)
Leitch, Victoria D (author)
Sparkes, Penny C (author)
Adoum, Anne-Tounsia (author)
Mannan, Naila S (author)
Komla-Ebri, Davide S K (author)
Pollard, Andrea S (author)
Dewhurst, Hannah F (author)
Hassall, Thomas A D (author)
Beltejar, Michael-John G (author)
Adams, Douglas J (author)
Vaillancourt, Suzanne M (author)
Kaptoge, Stephen (author)
Baldock, Paul (author)
Cooper, Cyrus (author)
Reeve, Jonathan (author)
Ntzani, Evangelia E (author)
Evangelou, Evangelos (author)
Ohlsson, Claes,1965Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xohlcl (author)
Karasik, David (author)
Rivadeneira, Fernando (author)
Kiel, Douglas P (author)
Tobias, Jonathan H (author)
Gregson, Celia L (author)
Harvey, Nicholas C (author)
Grundberg, Elin (author)
Goltzman, David (author)
Adams, David J (author)
Lelliott, Christopher J (author)
Hinds, David A (author)
Ackert-Bicknell, Cheryl L (author)
Hsu, Yi-Hsiang (author)
Maurano, Matthew T (author)
Croucher, Peter I (author)
Williams, Graham R (author)
Bassett, J H Duncan (author)
Evans, David M (author)
Richards, J Brent (author)
Göteborgs universitetCentre for Bone and Arthritis Research (creator_code:org_t)

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In:Nature genetics: Springer Science and Business Media LLC51, s. 258-2661546-17181061-4036

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By the author/editor: Morris, John A; Kemp, John P; Youlten, Scott E; Laurent, Laetiti ...; Logan, John G; Chai, Ryan C; show more...; Vulpescu, Nichol ...; Forgetta, Vincen ...; Kleinman, Aaron; Mohanty, Sindhu ...; Sergio, C Marcel ...; Quinn, Julian; Nguyen-Yamamoto, ...; Luco, Aimee-Lee; Vijay, Jinchu; Simon, Marie-Mic ...; Pramatarova, Alb ...; Medina-Gomez, Ca ...; Trajanoska, Kate ...; Ghirardello, Ele ...; Butterfield, Nat ...; Curry, Katharine ...; Leitch, Victoria ...; Sparkes, Penny C; Adoum, Anne-Toun ...; Mannan, Naila S; Komla-Ebri, Davi ...; Pollard, Andrea ...; Dewhurst, Hannah ...; Hassall, Thomas ...; Beltejar, Michae ...; Adams, Douglas J; Vaillancourt, Su ...; Kaptoge, Stephen; Baldock, Paul; Cooper, Cyrus; Reeve, Jonathan; Ntzani, Evangeli ...; Evangelou, Evang ...; Ohlsson, Claes, ...; Karasik, David; Rivadeneira, Fer ...; Kiel, Douglas P; Tobias, Jonathan ...; Gregson, Celia L; Harvey, Nicholas ...; Grundberg, Elin; Goltzman, David; Adams, David J; Lelliott, Christ ...; Hinds, David A; Ackert-Bicknell, ...; Hsu, Yi-Hsiang; Maurano, Matthew ...; Croucher, Peter ...; Williams, Graham ...; Bassett, J H Dun ...; Evans, David M; Richards, J Bren ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

Articles in the publication: Nature genetics

By the university: University of Gothenburg

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