Harvard 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.
Rosello-Diez, Alberto (författare)
Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA.
Leo, Paul J. (författare)
Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia.
Dahia, Chitra L. (författare)
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.
Park-Min, Kyung Hyun (författare)
Hosp Special Surg, Rheumatol Div, New York, NY 10021 USA.
Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.
van Duijn, Cornelia M. (författare)
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.
de Groot, Lisette C P G M(författare)
van der Velde, Nathalie (författare)
Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands.;Acad Med Ctr, Sect Geriatr, Dept Internal Med, NL-1105 Amsterdam, Netherlands.
Univ Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA.
Farber, Charles (författare)
Univ Virginia, Ctr Publ Hlth Genom, Dept Med, Charlottesville, VA 22908 USA.;Univ Virginia, Ctr Publ Hlth Genom, Dept Cardiovasc Med, Charlottesville, VA 22908 USA.
Grinberg, Daniel (författare)
Univ Barcelona, Dept Genet, E-08028 Barcelona, Spain.;Ctr Biomed Network Res Rare Dis CIBERER, U720, Barcelona 28029, Spain.;Univ Barcelona, Inst Biomed, Dept Human Mol Genet, E-08028 Barcelona, Spain.
LaCroix, Andrea Z. (författare)
Univ Calif San Diego, Womens Hlth Ctr Excellence Family Med & Publ Hlth, San Diego, CA 92103 USA.
Haessler, Jeff (författare)
Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA.
Chasman, Daniel I. (författare)
Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
Giulianini, Franco (författare)
Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
Rose, Lynda M. (författare)
Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
Ridker, Paul M. (författare)
Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.;Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA.
Eisman, John A. (författare)
Garvan Inst Med Res, Osteoporosis & Bone Biol Program, Sydney, NSW 2010, Australia.;Univ Notre Dame Australia, Sch Med Sydney, Sydney, NSW 6959, Australia.;NSW Univ, St Vincents Hosp, Sydney, NSW 2010, Australia.;NSW Univ, Sch Clin, Sydney, NSW 2010, Australia.
Nguyen, Tuan V. (författare)
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.
Center, Jacqueline R. (författare)
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.
Nogues, Xavier (författare)
Univ 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.
Garcia-Giralt, Natalia (författare)
Inst Hosp Mar Invest Med, Musculoskeletal Res Grp, Barcelona 08003, Spain.;Inst Hlth Carlos III, Cooperat Res Network Aging & Fragil RETICEF, Madrid 28029, Spain.
Prince, Richard L. (författare)
Sir Charles Gairdner Hosp, Dept Endocrinol & Diabet, Nedlands, WA 6009, Australia.;Univ Western Australia, Dept Med, Perth, WA 6009, Australia.
Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.
Cupples, L. Adrienne (författare)
Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA.
Ohlsson, Claes, 1965 (författare)
Gothenburg 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.
Greenwood, Celia M T(författare)
Jackson, Rebecca D. (författare)
Ohio State Univ, Dept Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA.
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.
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.
Ämnesord
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Ortopedi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Orthopaedics (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Hälsovetenskap -- Folkhälsovetenskap, global hälsa och socialmedicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Health Sciences -- Public Health, Global Health and Social Medicine (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Hälsovetenskap -- Näringslära och dietkunskap (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Health Sciences -- Nutrition and Dietetics (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Hälsovetenskap (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Health Sciences (hsv//eng)
