The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
Hsu, Yi-HsiangHebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.
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Estrada, KarolHarvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.;Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA.
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Rosello-Diez, AlbertoMem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA.
(författare)
Leo, Paul J.Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.
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Dahia, Chitra L.Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA.;Hosp Special Surg, Tissue Engn Regenerat & Repair Program, New York, NY 10021 USA.
(författare)
Park-Min, Kyung HyunHosp Special Surg, Rheumatol Div, New York, NY 10021 USA.
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Tranah, Gregory J.Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA.
(författare)
van Schoor, Natasja M.Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, EMGO Inst Hlth & Care Res, NL-1007 MB Amsterdam, Netherlands.,Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.
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Gardiner, Brooke B.Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.
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Cremin, KatieUniv Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.
(författare)
Auer, PaulUniv Wisconsin, Sch Publ Hlth, Milwaukee, WI 53726 USA.
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Hsu, LiFred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA.
(författare)
Ring, SueUniv Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England.
(författare)
Tung, Joyce Y.23andMe, Res Dept, Mountain View, CA 94041 USA.
(författare)
Enneman, Anke W.Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.
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van Duijn, Cornelia M.Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för samhällsmedicin och folkhälsa,Centre for Bone and Arthritis Research,Institute of Medicine, School of Public Health and Community Medicine,Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, NL-3000 CA Rotterdam, Netherlands.(Swepub:gu)xmelda
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de Groot, Lisette C P G M
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van der Velde, NathalieErasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Acad Med Ctr, Sect Geriatr, Dept Internal Med, NL-1105 Amsterdam, Netherlands.
(författare)
Center, Jacqueline R.Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW 2010, Australia.;NSW Univ, St Vincents Hosp, Sydney, NSW 2010, Australia.;NSW Univ, Sch Clin, Sydney, NSW 2010, Australia.
(författare)
Nogues, XavierUniv Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA.;Inst Hosp Mar Invest Med, Musculoskeletal Res Grp, Barcelona 08003, Spain.;Univ Autonoma Barcelona, Hosp Mar, Dept Internal Med, E-08193 Barcelona, Spain.
(författare)
Garcia-Giralt, NataliaInst Hosp Mar Invest Med, Musculoskeletal Res Grp, Barcelona 08003, Spain.;Inst Hlth Carlos III, Cooperat Res Network Aging & Fragil RETICEF, Madrid 28029, Spain.
(författare)
Prince, Richard L.Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia.;Univ Western Australia, Dept Med, Perth, WA 6009, Australia.
(författare)
Gauguier, DominiqueINSERM, UMRS 1138, Cordeliers Res Ctr, F-75006 Paris, France.;Univ Paris 06, Inst Cardiometab & Nutr, F-75013 Paris, France.
(författare)
Orwoll, Eric S.Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA.;Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA.
(författare)
Karasik, DavidHebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Bar Ilan Univ, Fac Med Galilee, IL-13010 Safed, Israel.
(författare)
Hinds, David A.23andMe, Res Dept, Mountain View, CA 94041 USA.
(författare)
Spector, TimKings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
(författare)
Cupples, L. AdrienneBoston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
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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,Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden.(Swepub:gu)xohlcl
(författare)
Greenwood, Celia M T
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Jackson, Rebecca D.Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA.
(författare)
Rowe, David W.Univ Connecticut, Ctr Hlth, Coll Dent Med, Dept Reconstruct Sci, Farmington, CT 06030 USA.
(författare)
Loomis, Cynthia A.NYU, Sch Med, Ronald O Perelman Dept Dermatol, New York, NY 10016 USA.;NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA.
(författare)
Evans, David M.Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.;Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England.
(författare)
Ackert-Bicknell, Cheryl L.NIA, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA.,Univ Rochester, Ctr Musculoskeletal Res, Rochester, NY 14642 USA.
(författare)
Joyner, Alexandra L.Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA.
(författare)
Duncan, Emma L.Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.;Royal Brisbane & Womens Hosp, Dept Diabet & Endocrinol, Brisbane, Qld 4029, Australia.
(författare)
Kiel, Douglas P.Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA.;Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Broad Inst MIT & Harvard, Boston, MA 02115 USA.;Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA.
(författare)