Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

被引：445

作者：

Zheng, Hou-Feng ^{[1
,2
,3
,4
,5
]}

Forgetta, Vincenzo ^{[1
,2
,3
,4
,5
]}

Hsu, Yi-Hsiang ^{[6
,7
,8
]}

Estrada, Karol ^{[7
,8
,9
,10
]}

Rosello-Diez, Alberto ^{[11
]}

Leo, Paul J. ^{[12
]}

Dahia, Chitra L. ^{[13
,14
]}

Park-Min, Kyung Hyun ^{[15
]}

Tobias, Jonathan H. ^{[16
,17
]}

Kooperberg, Charles ^{[18
]}

Kleinman, Aaron ^{[19
]}

Styrkarsdottir, Unnur ^{[20
]}

Liu, Ching-Ti ^{[21
]}

Uggla, Charlotta ^{[22
]}

Evans, Daniel S. ^{[23
]}

Nielson, Carrie M. ^{[24
,25
]}

Walter, Klaudia ^{[26
]}

Pettersson-Kymmer, Ulrika ^{[27
,28
,29
]}

McCarthy, Shane ^{[26
]}

Eriksson, Joel ^{[22
,30
]}

Kwan, Tony ^{[31
,32
]}

Jhamai, Mila ^{[9
]}

Trajanoska, Katerina ^{[9
,33
]}

Memari, Yasin ^{[26
]}

Min, Josine ^{[17
]}

Huang, Jie ^{[26
]}

Danecek, Petr ^{[26
]}

Wilmot, Beth ^{[34
,35
]}

Li, Rui ^{[1
,2
,3
,4
,5
]}

Chou, Wen-Chi ^{[6
,7
]}

Mokry, Lauren E. ^{[5
]}

Moayyeri, Alireza ^{[36
,37
]}

Claussnitzer, Melina ^{[6
,7
,8
,38
]}

Cheng, Chia-Ho ^{[6
]}

Cheung, Warren ^{[31
,32
,39
]}

Medina-Gomez, Carolina ^{[9
,33
,40
]}

Ge, Bing ^{[31
,32
]}

Chen, Shu-Huang ^{[31
,32
]}

Choi, Kwangbom ^{[41
]}

Oei, Ling ^{[9
,33
,40
]}

Fraser, James ^{[42
,43
]}

Kraaij, Robert ^{[9
,33
,40
]}

Hibbs, Matthew A. ^{[41
,44
]}

Gregson, Celia L. ^{[45
]}

Paquette, Denis ^{[42
,43
]}

Hofman, Albert ^{[33
,40
]}

Wibom, Carl ^{[46
]}

Tranah, Gregory J. ^{[24
,25
]}

Marshall, Mhairi ^{[12
]}

Gardiner, Brooke B. ^{[12
]}

机构：

[1] McGill Univ, Dept Med, Montreal, PQ H3A 1A2, Canada

[2] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1A2, Canada

[3] McGill Univ, Dept Epidemiol, Montreal, PQ H3A 1A2, Canada

[4] McGill Univ, Dept Biostat, Montreal, PQ H3A 1A2, Canada

[5] McGill Univ, Jewish Gen Hosp, Lady Davis Inst Med Res, Dept Med, Montreal, PQ H3T 1E2, Canada

[6] Hebrew SeniorLife, Inst Aging Res, Boston, MA 02131 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Broad Inst MIT & Harvard, Boston, MA 02115 USA

[9] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands

[10] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[11] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

[12] Univ Queensland, Diamantina Inst, Translat Res Inst, Princess Alexandra Hosp, Brisbane, Qld 4102, Australia

[13] Weill Cornell Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA

[14] Hosp Special Surg, Tissue Engn Regenerat & Repair Program, New York, NY 10021 USA

[15] Hosp Special Surg, Rheumatol Div, New York, NY 10021 USA

[16] Univ Bristol, Sch Clin Sci, Bristol BS10 5NB, Avon, England

[17] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England

[18] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA

[19] 23andMe, Res Dept, Mountain View, CA 94041 USA

[20] deCODE Genet, Dept Populat Genom, IS-101 Reykjavik, Iceland

[21] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[22] Univ Gothenburg, Ctr Bone & Arthrit Res, Dept Internal Med & Clin Nutr, Inst Med,Sahlgrenska Acad, S-41345 Gothenburg, Sweden

[23] Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94158 USA

[24] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97239 USA

[25] Oregon Hlth & Sci Univ, Bone Mineral Unit, Portland, OR 97239 USA

[26] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[27] Umea Univ, Dept Pharmacol, S-90187 Umea, Sweden

[28] Umea Univ, Dept Clin Neurosci, S-90187 Umea, Sweden

[29] Umea Univ, Dept Publ Hlth & Clin Med, SE-90187 Umea, Sweden

[30] Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, S-41345 Gothenburg, Sweden

[31] McGill Univ, Montreal, PQ H3A 0G1, Canada

[32] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[33] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands

[34] Oregon Hlth & Sci Univ, Oregon Clin & Translat Res Inst, Portland, OR 97239 USA

[35] Oregon Hlth & Sci Univ, Dept Med & Clin Informat, Portland, OR 97239 USA

[36] UCL, Farr Inst Hlth Informat Res, London NW1 2DA, England

[37] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[38] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02115 USA

[39] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

[40] NCHA, NGI, NL-2300 RC Leiden, Netherlands

[41] Univ Rochester, Ctr Musculoskeletal Res, Rochester, NY 14642 USA

[42] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada

[43] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada

[44] Trinity Univ, Dept Comp Sci, San Antonio, TX 78212 USA

[45] Univ Bristol, Musculoskeletal Res Unit, Bristol BS10 5NB, Avon, England

[46] Umea Univ, Dept Radiat Sci, S-90187 Umea, Sweden

[47] Univ Wisconsin, Sch Publ Hlth, Milwaukee, WI 53726 USA

[48] Univ Bristol, Sch Social & Community Med, Bristol BS8 2BN, Avon, England

[49] deCODE Genet, Dept Stat, IS-101 Reykjavik, Iceland

[50] Vrije Univ Amsterdam, Med Ctr, Dept Epidemiol & Biostat, NL-1007 MB Amsterdam, Netherlands

来源：

NATURE | 2015年 / 526卷 / 7571期

关键词：

WIDE ASSOCIATION LOCI; MINERAL DENSITY; HUMAN-DISEASES; VARIANTS; ENGRAILED-1; OSTEOPOROSIS; GENE;

D O I：

10.1038/nature14878

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 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 BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/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 +10.41 s.d., P-meta = 1 x 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.

引用

页码：112 / +

页数：20

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