TY - JOUR
T1 - Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
AU - Zheng, Hou-Feng
AU - Forgetta, Vincenzo
AU - Hsu, Yi-Hsiang
AU - Estrada, Karol
AU - Rosello-Diez, Alberto
AU - Leo, Paul J
AU - Dahia, Chitra L
AU - Park-Min, Kyung Hyun
AU - Tobias, Jonathan H
AU - Kooperberg, Charles
AU - Kleinman, Aaron
AU - Styrkarsdottir, Unnur
AU - Liu, Ching-Ti
AU - Uggla, Charlotta
AU - Evans, Daniel S
AU - Nielson, Carrie M
AU - Walter, Klaudia
AU - Pettersson-Kymmer, Ulrika
AU - McCarthy, Shane
AU - Eriksson, Joel
AU - Kwan, Tony
AU - Jhamai, Mila
AU - Trajanoska, Katerina
AU - Memari, Yasin
AU - Min, Josine
AU - Huang, Jie
AU - Danecek, Petr
AU - Wilmot, Beth
AU - Li, Rui
AU - Chou, Wen-Chi
AU - Mokry, Lauren E
AU - Moayyeri, Alireza
AU - Claussnitzer, Melina
AU - Cheng, Chia-Ho
AU - Cheung, Warren
AU - Medina-Gómez, Carolina
AU - Ge, Bing
AU - Chen, Shu-Huang
AU - Choi, Kwangbom
AU - Oei, Ling
AU - Fraser, James
AU - Kraaij, Robert
AU - Hibbs, Matthew A
AU - Gregson, Celia L
AU - Paquette, Denis
AU - Hofman, Albert
AU - Wibom, Carl
AU - Tranah, Gregory J
AU - Marshall, Mhairi
AU - Jensen, Jens-Erik B
AU - AOGC Consortium
PY - 2015/9/14
Y1 - 2015/9/14
N2 - 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.
AB - 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.
U2 - 10.1038/nature14878
DO - 10.1038/nature14878
M3 - Journal article
C2 - 26367794
SN - 0028-0836
VL - 526
SP - 112
EP - 117
JO - Nature
JF - Nature
IS - 7571
ER -