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

Författare och institution:
Hou-Feng Zheng (-); Vincenzo Forgetta (-); Yi-Hsiang Hsu (-); Karol Estrada (-); Alberto Rosello-Diez (-); Paul J. Leo (-); Chitra L. Dahia (-); Kyung Hyun Park-Min (-); Jonathan Tobias (-); Charles Kooperberg (-); Charlotte Uggla (Centre for Bone and Arthritis Research); Joel Eriksson (Centre for Bone and Arthritis Research); Dan Mellström (Centre for Bone and Arthritis Research & Institutionen för medicin, avdelningen för samhällsmedicin och folkhälsa); Liesbeth Vandenput (Centre for Bone and Arthritis Research); Claes Ohlsson (Centre for Bone and Arthritis Research & Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition); J. Brent Richards (-)
Publicerad i:
Nature, 526 ( 7571 ) s. 112-117
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
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.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
Klinisk medicin ->
Endokrinologi och diabetes ->
Klinisk medicin ->
Ytterligare information:
This article has more authors than registered here, please check the complete list:
Postens nummer:
Posten skapad:
2015-11-24 16:55
Posten ändrad:
2015-12-21 13:33

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